Long-acting Injectable Aripiprazole Research Articles

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder.

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

Towards precision medicine of long-acting aripiprazole through population pharmacokinetic modelling

Population pharmacokinetic (popPK) models constitute a valuable tool for characterizing the pharmacokinetic properties of once-monthly long-acting injectable aripiprazole (LAI aripiprazole) and quantifying the sources of variability in drug exposure. Our aim is to develop a popPK model of both aripiprazole and its metabolite dehydro-aripiprazole in patients treated with LAI aripiprazole, and to personalize the dosing regimen of aripiprazole across different sub-groups of patients. This is a prospective study investigating the pharmacokinetics of LAI aripiprazole. A total of 93 patients were included, 21 for model development and 71 for external model evaluation. A one-compartment model with linear absorption and elimination adequately described both aripiprazole and dehydro-aripiprazole concentrations. The weight of the patients has been shown to be the factor that most influences the absorption. However, the metabolizing phenotype for CYP2D6 and the concomitant treatment with strong inhibitors of this cytochrome have been shown to be the covariates that most influence total drug exposure. This is the first popPK model developed for LAI aripiprazole that includes aripiprazole and its main active metabolite, dehydroaripiprazole. It provides a personalized dosage recommendation that maximizes the probability of achieving optimal therapeutic concentrations and minimizes the difficulties associated with trial-and-error therapeutic strategies carried out in clinical practice.

Impact of long-acting injectable aripiprazole on the concomitant medication and antipsychotic polypharmacy: a retrospective, observational study of 127 patients with psychosis.

Antipsychotic polypharmacy (APP) has become prevalent over the years, but several concerns have been raised over APP. Accumulating evidence suggests that aripiprazole long-acting injectable (LAI) may reduce the rate of APP, but the association remains speculative. This retrospective observational study included 127 patients with psychosis and observed them for 1.8 ± 1.3 years, up to 4 years. Prescription data of antipsychotics (APs), mood stabilisers, benzodiazepines, and anti-extrapyramidal side effect medications were obtained at baseline and the last observation. Daily chlorpromazine equivalent (CPZ) dose of APs decreased from 124.40 ± 235.35 mg to 77.95 ± 210.36 mg ( P = 0.027). The daily dose of anticholinergics and beta-blockers also significantly decreased after introducing aripiprazole LAI. Among the patients having APP, the number of concurrent APs along with daily CPZ dose of APs decreased after initiation of aripiprazole LAI from 1.28 ± 0.62 to 0.85 ± 0.73 ( P < 0.001) and 298.33 ± 308.70 mg to 155.43 ± 280.53 mg ( P = 0.004), respectively. Treatment with aripiprazole LAI for up to 4 years in patients with psychosis was associated with a reduced number of prescribed APs in patients having an APP and a reduced dose of APs and concurrent psychotropic medications.

Prevention in Practice: Improving Communication on the Benefits of Treatments for Schizophrenia

AbstractIntroductionAntipsychotic treatment can help improve outcomes in schizophrenia by reducing the risk of relapse and psychiatric hospitalization, and increasing rates of remission and recovery, particularly when used early in the disease course. However, adherence to oral antipsychotics is often poor. Long-acting injectable (LAI) antipsychotic formulations are associated with significant improvements in treatment adherence compared with oral medications, but LAIs are not widely used in early-phase schizophrenia.MethodsAn educational training program, called “Prevention in Practice,” was developed to offer clinicians a range of innovative, web-based, patient-centered resources, including virtual role-play and educational films, that aim to improve communication between clinicians and patients and help progress care for patients with early-phase schizophrenia. The program was based on findings from the PRELAPSE study, in which clinicians received training to improve communication with patients. The PRELAPSE trial was a cluster randomized study conducted in 39 mental health centers across 19 US states. Sites were randomized to encourage treatment with the LAI aripiprazole once-monthly 400 mg (AOM 400) or to provide treatment as usual. Eligible patients had a diagnosis of schizophrenia, &lt;5 years of lifetime antipsychotic use, and were aged 18–35 years. The objective was to evaluate whether use of the LAI delayed time to first hospitalization in early-phase schizophrenia, compared with usual care. Clinicians received training on the rationale for LAI use in early psychosis, transitioning to LAIs, and discussing LAIs with patients and families. Communication training included the principles of shared decision-making, suggested responses to frequently asked questions, and role-playing.ResultsIn PRELAPSE, the sites randomized to encourage LAI treatment enrolled 234 patients and the sites randomized to usual care enrolled 255 patients. Training clinicians to improve their communication with patients made a difference—91% of patients with early-phase schizophrenia were willing to use LAI treatment at least once in the first 3 months of the study. Furthermore, the results showed that AOM 400 significantly prolonged time to first psychiatric hospitalization compared with usual care (hazard ratio: 0.56 [95% confidence interval: 0.34, 0.92]; p=0.02).ConclusionsOffering clinicians training to improve their communication with patients, through techniques such as shared decision-making and motivational interviewing, may increase LAI use in early-phase schizophrenia. ”Prevention in Practice” is now available in in different countries and languages.FundingOtsuka Pharmaceutical Development &amp; Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).

Differences in autonomic nervous system activity between long-acting injectable aripiprazole and oral aripiprazole in schizophrenia

BackgroundDistinct oral atypical antipsychotics have different effects on autonomic nervous system (ANS) activity. Among them, oral aripiprazole has been linked to dysfunction of the ANS in schizophrenia. Long-acting injectable aripiprazole is a major treatment option for schizophrenia, but the effect of the aripiprazole formulation on ANS activity remains unclear. In this study, we compared ANS activity between oral aripiprazole and aripiprazole once-monthly (AOM) in schizophrenia.MethodsOf the 122 patients with schizophrenia who participated in this study, 72 received oral aripiprazole and 50 received AOM as monotherapy. We used power spectral analysis of heart rate variability to assess ANS activity.ResultsPatients who received oral aripiprazole showed significantly diminished sympathetic nervous activity compared with those who received AOM. Multiple regression analysis revealed that the aripiprazole formulation significantly influenced sympathetic nervous activity.ConclusionCompared with oral aripiprazole, AOM appears to have fewer adverse effects, such as sympathetic nervous dysfunction.

Long-acting new generation antipsychotics in the maintenance treatment of bipolar disorders

IntroductionMaintaining remission, preventing from future episodes, better treatment adherence and improving the quality of life are main aims of long-term treatment in bipolar disorders (BD). In recent years, new generation long-acting injectable (LAI) antipsychotics have been frequently used in maintenance treatment for bipolar disorders.ObjectivesWe aimed to review socio-demographic and clinical characteristics of bipolar patients taking LAI treatment for maintenance treatment.MethodsClinical records of 56 bipolar patients who are on LAI treatment and followed in Mazhar Osman Mood Clinic (MOMC) of Selcuk University Medical Faculty were evaluated. Descriptive statistical analysis was performed with Statistical Package for the Social Sciences (SPSS).ResultsNearly half of the patients were male (n:29, 52%). 49,1% of the patients were married. The mean age was 37.1±12.2 years and the mean duration of education was 11.1±4.2 years. All of the patients were diagnosed with bipolar 1 disorder. Most of the patients (64,7%) was on aripiprazole LAI while remaining was receiving paliperidone LAI for maintenance treatment. We found a significant reduction in the number of manic episodes after long-acting treatment (p&lt;0.001), but we could not find any difference for depression. Ten of the patients discontinued the treatment due to the side effects, extrapyramidal side effects were the most common side effects. Eight of the patients were switched from paliperidone treatment to aripiprazole treatment due to side effects, especially hyperprolactinemia. Relapse was observed in 46,4% of the patients and there was no difference between aripiprazole and paliperidone in terms of relapse rate.ConclusionsLAI new generation antipsychotics are taking place in long-term treatment of bipolar disorder via improving treatment adherence. Side effect profile of aripiprazole and paliperidone are different. However, we could not find any difference between two drugs in terms of side effects and relapse rates. Small sample size and shorter duration of follow-up should be considered as limitations.Disclosure of InterestNone Declared

The effect of long-acting injectable antipsychotics on QRISK3 in patients with bipolar disorder and schizophrenia

IntroductionPsychiatric diseases are often accompanied by medical comorbidities, and cardiovascular system disease is one of the most important causes of death in bipolar disorder (BD) and schizophrenia (SCH) [1]. The QRISK3 algorithm calculatesa person’s risk of developing cardiovascular disease over the next ten years and it has been used in psychiatric research in recent years [2].ObjectivesIn this study, we aimed to evaluate the relationship between cardiovascular risks (by using QRISK3 algorithm) and treatment options in patients of BD and SCH.MethodsThirty-six patients with bipolar disorder and thirty-two patients with schizophrenia recruited between the years 2016-2022. All of the patients were treated with long-acting injectable (LAI) antipsychotics. Sociodemographic information, clinical features and medical treatment agents of individuals were recorded. The risk of development of cardiac disease of the patients were evaluated by the QRISK3 algorithm. Descriptive and regression statistical analysis was performed with Statistical Package for the Social Sciences (SPSS).ResultsMore than half of the patients were male (n= 39, 57.4%) and single (n= 40, 58.8%). The mean duration of education was 9.2 ±3.5 years and the mean age was 39.7 ±11.9 years of the patients. Nearly half of the patients had a diagnosis of BD (n= 36, 52.9%) while others had SCH (n:32, 47.1%). Most of the patients were treated with LAI of aripiprazole (n= 36, 59.2%) and the rest of them were treated with LAI of paliperidone (n= 32, 40.8%). When demographic and clinical data of BD and SCH patients were compared, there was no significant difference in terms of age. However, SCH patients had a longer disease duration (t= 2.56, p= 0.013) and more hospitalization (t= 3.35, p= 0,002) than BD patients. Our findings showed positive correlations between age (r= 0.74, p&lt;0.01), duration of disease (r= 0.57, p&lt; 0.01), and duration of LAI use (r= 0.55, p&lt; 0.01) with QRISK. A regression analysis to examine related factors associated with QRISK found that having a diagnosis of schizophrenia (β= 0.27, t= 2.58; p= 0.01) and a long disease duration (β= 0.67, t= 6.50, p&lt; 0.01) were associated with the development of cardiovascular disease. However, there was no relationship between LAIs (paliperidone vs aripiprazole) used in the treatment and QRISK.ConclusionsThe significant correlation found between duration of disease and QRISK -that indicate the risk of development of cardiac disease- confirming the progressive nature of the BD and SCH. Moreover, the significant correlation between SCH and QRISK suggests that SCH is a chronic and severe disease that causes more cardiac dysfunction than BD. However, we could not find a significant difference between LAIs in terms of QRISK, these results can be changed by evaluating other variables such as comorbidities, other medical treatments and physical activities in future research.Disclosure of InterestNone Declared

Effectiveness of Switching to Long-acting Injectable Aripiprazole in Patients with Recent-onset and Chronic Schizophrenia.

This study investigated the effectiveness of switching to once-monthly long-acting injectable (LAI) aripiprazole from other second-generation antipsychotics including LAI paliperidone palmitate in both recent-onset and chronic schizophrenia patients. This was a 24-week prospective, open-label, flexible dose-switching study in patients with schizophrenia. Scores on the Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance (PSP) scale, Clinical Global Impression (CGI), Subjective Well-being Under Neuroleptics-Short Form (SWN-K), and a computerized emotional recognition test (ERT) were evaluated. Subjects were divided into two groups (recent onset and chronic) based on 5 years' duration of the illness. Among the 82 patients participating, 67 (81.7%) completed the 24-week study. The discontinuation rate after switching to LAI aripiprazole did not differ according to clinical characteristics including type of previous antipsychotics. Scores on the PANSS, PSP, SWN-K, CGI, and ERT were significantly improved after a switch to LAI aripiprazole without exacerbation of metabolic parameters and bodyweight. The improvements in the PANSS, PSP, and CGI scores were significantly greater in patients with recent-onset than in those with chronic schizophrenia; the improvement in metabolic parameters was significantly greater in the latter group. High rates of successful switching to LAI aripiprazole from other antipsychotics suggest its good tolerability and effectiveness. Improvements in psychopathology and social functioning were more evident in patients with recent- onset schizophrenia, and improvements in metabolic abnormalities were more prominent in patients with chronic schizophrenia.

Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST)

Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. Lundbeck and Otsuka.

Weight changes in people with early psychosis treated with oral or long-acting injectable aripiprazole

ObjectivesWeight gain remains a major problem in young people with psychosis treated with antipsychotic medication. Aripiprazole is now available in monthly long-acting injection (LAI) and daily oral tablet formulation, but information is lacking about differences in weight gain between the two formulations. We monitored for up to 24 months the weight changes associated with oral or LAI-administered aripiprazole and in a group who not prescribed any antipsychotic medication. MethodsParticipants included 109 young people with early psychosis (n = 30 Oral, 41 LAI, 38 Nil antipsychotic) with a treatment completion median time of 15 months. Weight (kilogram) and body mass index (BMI) were recorded at 3 monthly intervals. Multilevel modelling analyses assessed the contribution of time and group on weight change. ResultsParticipants taking nil antipsychotics did not gain weight over time, while the two aripiprazole groups gained a combined average of 7.1 kg (SD = 5.0) or 1.9 BMI (SD = 0.4). An examination of formulation effects showed a significantly greater rate of change over time in the Oral group with a weight increase of approximately 11.0 kg (SD = 8.2) or 3.5 BMI (SD = 0.7, compared to the LAI group with a gain of 3.7 kg (SD = 2.1) or 0.8 BMI (SD = 0.1) in the LAI group. These differences could not be explained by demographic or clinical characteristics, medication dosage, or baseline weight. ConclusionsWhile aripiprazole is generally considered relatively benign in terms of weight, it still poses a significant risk especially for people with early psychosis. However the current study suggests that the risk may be lower in those treated with LAI than with Oral formulation, consolidating the clinical utility of LAI.

Efficacy and tolerability Aripiprazole once-monthly long-acting injectable in schizophrenia. Two-injection start regimen

IntroductionAripiprazole once-monthly is a long-acting intramuscular injectable formulation of aripiprazole. The starting dose can be administered by following one of two regimens: • One injection start: On the day of initiation, administer one injection of 400 mg Aripiprazole once monthly and continue treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutive days • Two injection start (New regimen): On the day of initiation, administer two separate injections of 400 mg Aripiprazole once monthly at separate injection sites, along with one 20 mg dose of oral aripiprazole.ObjectivesTo assess the effectiveness and tolerability of Aripiprazole long-acting injectable (ALAI) in patients with schizophrenia. The starting dose was administered following the two injection start regimenMethodsSample:10 patients with schizophrenia (DSM 5 criteria) who started treatment with ALAI. The starting dose was administered following the two injection start regimen. On a tri-monthly basis, the following evaluations were performed during a follow-up period of 6 months: The Clinical Global Impression-Schizophrenia scale (CGI-SCH), treatment adherence, the number of hospitalizations and Side effects reportedResultsMean variations from baseline scores at 6 months was (-1.1 ±0.89) on the GCI-SCH. The percentage of patients who remained free of admissions at the end of the 6 months was 90%. The rate of adherence to treatment after 6 months was 80%. The most frequent side effect was transient mild insomnia (20%) .ConclusionsAripiprazole long-acting injectable (The starting dose was administered following the two injection start regimen) is effective, safe and well tolerated in clinical practice conditionsDisclosureNo significant relationships.

Aripiprazole lai two-injection start in a 16 year-old with Schizophrenia

IntroductionAripiprazole LAI is approved for the treatment of schizophrenia in adults. Recently, Europe and Canada approved the use of the two-injection start (TIS) regimen: two separate injections of 400 mg long-acting aripiprazole along with a single 20 mg dose of oral aripiprazole. Aripiprazole showed efficacy in the treatment of adolescents with acute schizophrenia in several controlled trials, leading to its approval for 13-17 year-old adolescents with schizophrenia by the EMA. However, the LAI formulation still remains off-label in adolescents.ObjectivesTo demonstrate the efficacy and safety of the TIS regimen of aripiprazole LAI formulation in a 16 year-old adolescent with schizophrenia.MethodsWe evaluated the symptoms of schizophrenia and general severity by means of the PANSS and CGI scales. The scales were administered at hospital admission, after 3 weeks, 5 weeks, and at 4-weeks follow-up.ResultsAt the admission the patient PANSS total score was 136, the CGI score of 7. Aripiprazole was started and up-titrated to 30 mg/day. After 3 weeks, the positive symptoms were significantly reduced; due to the persistence of negative symptoms, clozapine 100 mg/day was added. At week 5 the PANSS total score decreased to 81. Due to poor insight we proposed aripiprazole LAI with the two-injection start. One month later, global functioning and illness insight improved; PANSS score was 43, CGI score 2. There was no evidence of akathisia or other side effects.ConclusionsAripiprazole LAI showed good efficacy and tolerability in an adolescent with schizophrenia. The two-injection start regimen was a safe and viable option.DisclosureNo significant relationships.

Long-acting new generation antipsychotics in the maintenance treatment of bipolar disorders

IntroductionMaintaining remission, preventing from future episodes, better treatment adherence and improving the quality of life are main aims of long-term treatment in bipolar disorders (BD). In recent years, new generation long-acting injectable (LAI) antipsychotics have been frequently used in maintenance treatment for bipolar disorders.ObjectivesWe aimed to review socio-demographic and clinical characteristics of bipolar patients taking LAI treatment for maintenance treatment.MethodsClinical records of 44 bipolar patients who are on LAI treatment and followed in Mazhar Osman Mood Clinic (MOMC) of Selcuk University Medical Faculty were evaluated.ResultsNearly half of the patients were male (n:24, 54%). 43,2% of the patients were married. The mean age was 36.6±11.9 years and the mean duration of education was 11.5±3.9 years. All of the patients were diagnosed with bipolar 1 disorder. Most of the patients (65.9%) was on aripiprazole LAI while remaining was receiving paliperidone LAI for maintenance treatment. Ten of the patients discontinued the treatment due to the side effects and extrapyramidal side effects was the most common side effect. Relapse was observed in 25% of the patients and there was no difference between aripiprazole and paliperidone in terms of relapse rate.ConclusionsLAI new generation antipsychotics are taking place in long-term treatment of bipolar disorder via improving treatment adherence. Side effect profile of aripiprazole and paliperidone are different. However, we could not find any difference between two drugs in terms of side effects and relapse rates. Small sample size and shorter duration of follow-up should be considered as limitations.DisclosureNo significant relationships.

A new day, a new treatment. A case report

IntroductionWe present the case of a 21 year-old male, with history of a psychotic episode, currently with monthly follow-up in an outpatient facility, with a favorable clinical evolution after one year of intensive follow-up. In the context of abandonment of his medication and a problematic family situation, the patient starts to show suspicious, with insomnia and a progressive social isolation. Despite an attempt of ambulatory treatment with oral aripiprazole, showing good tolerance, the patient refuses such treatment, showing active clinical psychotic with great distress and behavioral repercussion, finally requiring hospital admission.ObjectivesTo perform a literature review about the treatment initiation with two vials of aripiprazole long-acting injection.MethodsLiterature review of scientific articles using Pubmed as search engine. We considered articles published both in English and Spanish.ResultsDuring hospital stay, treatment with 2 intramuscular injections of 400mg of aripiprazole is started, combined with a single dose of oral aripiprazole 20mg on day 1, assuring correct dosing, with good tolerance and favoring therapeutic adherence. Progressively, the patient starts to feel calmer, adequate, collaborative and emotionally stable, recuperating chronobiological rhythms, with remission of the hallucinations and appearing more distant from delusions.ConclusionsAccording to the currently available studies, the use of this posology could avoid the potential impact that lack of adherence to oral treatment could have in the therapeutic outcome, assuring a correct dosing and favoring adherence from day 1. Furthermore, this would help simplify the medication regiment for patients, physicians and caregivers.DisclosureNo significant relationships.

Combination therapy of modified electroconvulsive therapy and long-acting injectable aripiprazole for dopamine supersensitivity psychosis: a case report

ABSTRACT In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

Impact of jet pulverization and wet milling techniques on properties of aripiprazole long-acting injection and absorption mechanism research in vivo

This study aims to explore the influence of wet milling and jet pulverization on the aripiprazole microcrystalline long-acting injection. Crystal form and particle size distribution were taken as inspection indicators in vitro, and process parameters were optimized. The formulation prepared by wet milling (AMLAI-WM) was shown to undergo a slight conversion of crystal form by DSC, PXRD, TG, FT-IR and have a wider particle size distribution with D50 and Span values of 2.967 μm and 3.457 compared to the formulation fabricated by jet pulverization (AMLAI-JP) with 2.887 μm and 2.258 respectively. In addition, the in vitro release of AMLAI-WM was faster, whereby the pharmacokinetic data indicated that AMLAI-WM was absorbed more quickly within five days with AUC0-5d of 5243.7 μg·L-1·h and 4818.28 μg·L-1·h, respectively. Furthermore, no statistically significant differences in Cmax, tmax and AUC between AMLAI-JP and the commercial formulation (Abilify Maintena™) were found. The absorption mechanism was studied and showed a 1.4-fold later Tmax after depletion of macrophages and significantly lower Cmax and AUC after inhibiting angiogenesis, indicating inflammatory granuloma could facilitate drug plasma exposure. Overall, we demonstrated that jet pulverization was a good strategy for long-acting microcrystalline injection, and that the absorption behavior was affected by both particle size distribution and inflammatory granuloma.

An Integrated Pharmacokinetic-Pharmacodynamic-Pharmacoeconomic Modeling Method to Evaluate Treatments for Adults with Schizophrenia.

IntroductionSchizophrenia is a chronic mental disorder that worsens with each relapse. Long-acting injectable (LAI) antipsychotics may prevent the exacerbation of symptoms and occurrence of relapses through improved continuity of care. Different dose regimens are available for the LAIs aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), but their cost effectiveness is unclear.ObjectivesThe study aim was to compare costs and effects (relapses) of the different aripiprazole LAI dose regimens to inform clinical and US payer decisions.MethodsA state-transition model calculated the outcomes of eight LAI dose regimens based on their relapse rates. As effectiveness data from randomized controlled trials were unavailable, relapse rates were modeled using pharmacokinetic and pharmacodynamic evidence. These described blood plasma levels of aripiprazole as a function of AM and AL dose regimens and described the probability of relapse as a function of aripiprazole blood plasma levels. The analysis had a time horizon of 1 year and took the US healthcare payer perspective. The incremental cost per relapse avoided and the probability of cost effectiveness were calculated in deterministic and probabilistic analyses. Scenario analyses explored the model’s main assumptions, and results were validated against external data and other cost-effectiveness analyses.ResultsMonthly administration of AM 400 mg consistently yielded the lowest predicted number of relapses across deterministic, probabilistic, and scenario analyses. The costs of treatment and relapses were projected to be the lowest with a monthly administration of AL 441 mg. The incremental cost per relapse avoided with AM 400 mg ranged from AM 400 mg being dominant to $US83,300. From willingness-to-pay thresholds of $US30,000 per relapse avoided, the probability of cost effectiveness was highest for AM 400 mg. The validation showed alignment with external data.ConclusionThe analysis highlighted the robustness of the novel framework based on pharmacokinetic and pharmacodynamic evidence and demonstrated an application in a postmarketing setting.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01077-8.

Real-World Data Show Patients With Schizophrenia Adhere Better to Clozapine and LAIs

Back to table of contents Previous article Next article Clinical & ResearchFull AccessReal-World Data Show Patients With Schizophrenia Adhere Better to Clozapine and LAIsNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:8 Oct 2021https://doi.org/10.1176/appi.pn.2021.9.32AbstractAn analysis of national VA health databases shows clozapine along with long-acting formulas of aripiprazole and paliperidone have lower discontinuation rates than oral olanzapine, while oral quetiapine and ziprasidone have higher discontinuation rates.Patients with schizophrenia may be less likely to discontinue treatment if prescribed clozapine or long-acting injectable (LAI) formulations of second-generation antipsychotics, according to a report in AJP in Advance. The findings, which also revealed that patients who were taking multiple antipsychotics (polypharmacy) had lower discontinuation rates, were based on data from the U.S. Department of Veterans Affairs (VA).Though the data was limited to veterans, lead author Marc Weiser, M.D., head of the Division of Psychiatry at Sheba Medical Center in Ramat Gan, Israel, noted the findings mirrored those of a 2017 study that used Swedish medical data. “Replicating research findings is difficult,” Weiser noted. “When you have nearly identical outcomes from two studies done by different investigators in different countries using different patient populations, it points to the results being broadly applicable.”Weiser and colleagues compiled VA clinical and pharmacy data from all patients who received a schizophrenia diagnosis and at least one antipsychotic prescription lasting 60 days or more between October 2010 and September 2015. To keep the data robust, the investigators focused on antipsychotics with at least 150 prescriptions during the analysis period. The final sample included 37,368 patients with 62,056 antipsychotic prescriptions among 15 categories: nine oral medications (aripiprazole, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, and all first-generation antipsychotics), five LAI formulations (first-generation drugs fluphenazine and haloperidol and second-generation aripiprazole, paliperidone, and risperidone), and patients receiving polypharmacy.The investigators compared the treatment discontinuation rates and hospital admission rates associated with all the medications relative to olanzapine. Weiser noted olanzapine was chosen as the reference since it is considered the most well-tolerated oral antipsychotic and it was used as the reference drug in the 2017 Swedish study.After adjusting for patient sociodemographic factors, Weiser and colleagues found that five groups had a lower risk of treatment discontinuation than olanzapine. These included patients taking clozapine (with nearly 60% less discontinuation risk than olanzapine), a trio of second-generation LAIs (aripiprazole, paliperidone, and risperidone), and patients on polypharmacy. Patients taking oral quetiapine, oral ziprasidone, oral aripiprazole, oral risperidone, and oral first-generation antipsychotics all had higher risks of discontinuation than those taking olanzapine. In a secondary analysis, the investigators found that all three second-generation LAIs were associated with lower risks of discontinuation with the oral formulations of the medications.Weiser told Psychiatric News that he was not surprised by the findings that clozapine was associated with a lower risk of treatment discontinuation than the other antipsychotics. “Since clozapine requires patients to check in regularly, physicians tend to prescribe it to patients who they believe will be compliant; there is a pre-screening process built in.”The polypharmacy findings were a bit more surprising, he noted. “Giving patients multiple antipsychotics is considered a no-no in clinical settings, but this finding supports that giving the right combination of drugs can boost their effectiveness,” he said. Future studies should look at which combinations may offer the most symptom improvement along with lowest risks of side effects.In contrast to the discontinuation findings, none of the medications were found to reduce the risk of psychiatric hospitalization compared with olanzapine. Weiser noted this was the one of the few divergences from the Swedish study, which found clozapine to be superior to olanzapine.While no antipsychotics were superior to olanzapine in terms of hospitalizations, several were associated with increased hospitalization risk: these included oral and LAI first-generation antipsychotics, as well as oral lurasidone, quetiapine, and ziprasidone.Weiser noted that he was particularly concerned about the quetiapine finding, being that this was the second most-prescribed medication in the sample (behind oral risperidone) and this medication was associated with a 36% increased risk of hospitalization. “It is interesting since in the general population, quetiapine is not used that extensively for schizophrenia,” he said. Rather, quetiapine is more commonly prescribed off-label for conditions like anxiety or insomnia.This study was supported by the Stanley Medical Research Institute. Weiser also serves on the staff of the Stanley Institute. ■“Differences in Antipsychotic Treatment Discontinuation Among Veterans With Schizophrenia in the U.S. Department of Veterans Affairs” is posted here.The 2017 analysis, “Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia” is posted here. ISSUES NewArchived

Real-World Outcomes and Costs Following 6 Months of Treatment with the Long-Acting Injectable (LAI) Aripiprazole Lauroxil for the Treatment of Schizophrenia.

BackgroundContinuous antipsychotic therapy is recommended as part of long-term maintenance treatment of schizophrenia, and gaps in antipsychotic treatment have been associated with increased risks of relapse and rehospitalization. Because the use of long-acting injectable (LAI) antipsychotics may reduce the likelihood of undetected medication gaps, initiating an LAI medication may affect resource utilization and costs. The LAI aripiprazole lauroxil (AL) was approved in the United States (US) in 2015 for the treatment of schizophrenia in adults.ObjectiveThe objective of this retrospective observational cohort study was to examine treatment patterns, resource utilization, and costs following initiation of AL for the treatment of schizophrenia in adults.MethodsA retrospective analysis of Medicaid claims data identified a cohort of patients (N = 485) starting AL shortly after Food and Drug Administration approval in October 2015. Treatment patterns, resource utilization, and costs were compared 6 months before and after treatment initiation. Subgroup analyses were conducted based on the type of antipsychotic (LAI, oral, or none) received before initiation of AL.ResultsOver 6 months of follow-up, patients received an average of 4.6 injections out of a maximum of six (77%). After initiating AL, all-cause inpatient admissions decreased by 22.4%; other significant reductions were observed in mental health–related admissions and emergency room (ER) visits. All-cause inpatient costs decreased by an average of US$2836 per patient (p < 0.05) in the 6-month post-AL period, whereas outpatient pharmacy costs increased by US$4121 (p < 0.05), resulting in no significant difference in overall costs between the pre- and post-AL periods. The subgroup of patients who had been prescribed an oral antipsychotic before starting AL had significant reductions in proportion of patients with inpatient and ER visits and costs, but also reported a significant increase in pharmacy costs.ConclusionsAL was associated with a significant reduction in inpatient costs and an increase in outpatient pharmacy costs, resulting in no changes in total healthcare costs over 6 months. The adherence rate and reductions in inpatient use may indicate the potential for greater clinical stability among patients initiated on AL compared with their previous treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00849-2.

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics.

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.