Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies.
Kishimoto Taishiro,Nitta Masahiro,Borenstein Michael,Kane John M,Correll Christoph U
The Journal of clinical psychiatry
OBJECTIVE:Recent, large, randomized controlled trials (RCTs) showed no benefit of long-acting injectable (LAI) antipsychotics over oral antipsychotics in preventing relapse in schizophrenia, nor did a recent meta-analysis incorporating these studies. However, RCTs might enroll a disproportionate number of patients with better treatment adherence and lower illness severity. Mirror-image studies, which compare periods of oral antipsychotic versus LAI treatment in the same patients, might therefore better reflect the real-world impact of LAIs. DATA SOURCES:A systematic literature search without language restriction was conducted using MEDLINE/PubMed, Cochrane Library, Web of Science, PsycINFO, and CINAHL until May 31, 2012. Search terms included synonyms of (1) antipsychotic(s) AND (2) schizophrenia and related disorders AND (3) depot, (long-acting) injection(s), microsphere, decanoate, palmitate, enanthate. STUDY SELECTION:Of 5,483 identified citations, 607 articles were fully inspected, and 582 were ineligible. Finally, 25 mirror-image studies from 28 countries that followed 5,940 patients with schizophrenia for ≥ 12 months (≥ 6 months each on oral antipsychotic and LAI treatment) met the inclusion criteria and were analyzed. DATA EXTRACTION:Coprimary outcomes were hospitalization risk and number of hospitalizations. Secondary outcomes included hospitalization days and length of stay. DATA SYNTHESIS:LAIs showed strong superiority over oral antipsychotics in preventing hospitalization (16 studies, N = 4,066; risk ratio = 0.43; 95% CI, 0.35-0.53; P < .001) and in decreasing the number of hospitalizations (15 studies, 6,342 person-years; rate ratio = 0.38; 95% CI, 0.28-0.51; P < .001). This strong advantage was also observed for secondary outcomes and in multiple clinically relevant subpopulations and treatment groups. CONCLUSIONS:Results from mirror-image studies in patients eligible for clinical use of LAIs showed strong superiority of LAIs compared to oral antipsychotics in preventing hospitalization. The results were in contrast to the recent meta-analysis of RCTs, which showed no superiority of LAIs. Given the possible biases in mirror-image studies, such as expectation bias, natural illness course, and time effect, a cautious interpretation is required. Nevertheless, the population in mirror-image studies better reflects the population receiving LAIs in clinical practice.
Decision-making Capacity for Treatment of Psychotic Patients on Long Acting Injectable Antipsychotic Treatment.
Nystazaki Maria,Pikouli Katerina,Tsapakis Eva-Maria,Karanikola Maria,Ploumpidis Dimitrios,Alevizopoulos Giorgos
Archives of psychiatric nursing
OBJECTIVE:Providing informed, consent requires patients' Decision-Making Capacity for treatment. We evaluated the Decision Making Capacity of outpatients diagnosed with schizophrenia and schizoaffective disorder on treatment with Long Acting Injectable Antipsychotic medication. METHOD:This is a retrospective, cross-sectional, correlational study conducted at two Depot Clinics in Athens, Greece. Participants included 65 outpatients diagnosed with schizophrenia and schizoaffective disorder on treatment with Long Acting Injectable Antipsychotics. RESULTS:Over half of the participants showed poor understanding of the information given regarding their disease and treatment (Understanding subscale), however >70% seemed to comprehend the relevance of this information to their medical condition (Appreciation subscale). Moreover, half of the participants reported adequate reasoning ability (Reasoning subscale), whilst patients who gained >7% of their body weight scored statistically significantly higher in the subscales of Understanding and Appreciation. CONCLUSION:Our results suggest that there is a proportion of patients with significantly diminished Decision Making Capacity, hence a full assessment is recommended in order to track them down. Further research is needed to better interpret the association between antipsychotic induced weight gain and Decision Making Capacity in patients suffering from schizophrenia or schizoaffective disorder.
Long-acting injectable antipsychotics in early psychosis: a literature review.
Emsley Robin,Chiliza Bonginkosi,Asmal Laila,Mashile Mpogisheng,Fusar-Poli Paolo
Early intervention in psychiatry
AIM:There are sound reasons for considering the use of long-acting injectable antipsychotics early in the course of schizophrenia. We reviewed available literature on the subject. METHOD:We conducted an electronic database search and critically reviewed all studies in which a long-acting injectable antipsychotic was evaluated in early psychosis patients. RESULTS:There is a need for well-designed studies as most of those reported were open-label and non-comparative, and samples were frequently small. CONCLUSIONS:The available evidence does suggest that long-acting injectable antipsychotics can be used safely and effectively in early stages of the illness, and that they may be associated with better outcomes than with oral medications. However, this is largely supported by evidence from naturalistic cohort studies and a small number of controlled trials of risperidone long-acting injection. Evidence for olanzapine and paliperidone long-acting injectables in particular is limited.
A further consideration on long-acting injectable versus oral antipsychotics in the treatment of schizophrenia: a narrative review and critical appraisal.
Expert opinion on drug delivery
INTRODUCTION:Many patients with schizophrenia exhibit difficulties in maintaining adherence to oral antipsychotics, calling for more reliable drug delivery systems. AREAS COVERED:While non-randomized studies have indicated consistent effectiveness of long-acting injectable antipsychotics (LAIs) over oral counterparts to prevent negative consequences such as relapse, hospitalization and all-cause discontinuation, efficacy results from randomized controlled comparative trials have not been that impressive. The results rely heavily on the study design and the population studied. Further, LAIs are frequently used as an adjunctive to ongoing other antipsychotics or psychotropics, but not solely, in the real world. EXPERT OPINION:To put LAI-oral comparisons into clinical context, the following information is urgently necessary: (1) How LAIs compare with each other in head-to-head comparisons? (2) How effective is it to switch among different LAIs? (3) How early in the treatment stage should LAIs be utilized? (4) How long the interval of LAI administration can be extended? (5) How LAIs compare with clozapine in head-to-head comparisons? (6) How effective are LAIs when clozapine is ineffective? (7) How effective is clozapine when LAIs are ineffective? (8) How effective is it to combine clozapine and LAIs when neither is effective alone? This paper narratively discusses these critical perspectives.
Does the frequency of administration of long acting injectable antipsychotics impact psychiatric outcomes and adverse effects: A systematic review and meta-analysis.
Ting Erich,Kamalvand Sebnem,Shang Dongxu,Siskind Dan,Kisely Steve
Journal of psychiatric research
Dosing regimens for depot antipsychotics range from two-to twelve-weekly administration. There are limited meta-analytic data regarding the effect of different injection frequencies of the same depot antipsychotic at the equivalent dose on psychiatric outcomes and adverse effects. This study investigated differences in psychiatric outcomes and adverse effects between different frequencies of depot antipsychotics through a systematic review and meta-analysis. We performed a systematic search of MEDLINE, EMBASE, Cochrane database, PsycINFO and two Chinese databases for RCTs that compared the frequency of depot antipsychotic administration. The primary outcome was psychiatric symptomatology, with secondary outcomes of quality of life, admission rates, adverse drug reactions, cost-effectiveness and compliance. Twelve studies were included in the meta-analysis. Most studies compared two- and four-weekly injections (n = 10). Different injection frequencies did not lead to differences in clinical outcomes or adverse events. However, two-weekly injections led to significantly greater improvements on the CGI-S scale than four-weekly administration. A sensitivity analysis by removing low quality studies showed lower incidence of somnolence and injection site pain for 2-weekly compared with 4-weekly injections. There were limited data on admission rates and no RCT data on cost-effectiveness or compliance. While there is limited evidence on secondary measures to support 2-weekly over 4-weekly injections, patient choice and convenience should remain the priority when considering certain antipsychotics. Cost-effectiveness and adherence should also be considered, although further studies are required to further evaluate these parameters.
The effectiveness of long-acting injectable antipsychotics versus oral antipsychotics in the maintenance treatment of outpatients with chronic schizophrenia.
Fang Su-Chen,Liao Ding-Lieh,Huang Cheng-Yi,Hsu Chun-Chi,Cheng Shu-Li,Shao Yu-Hsuan J
OBJECTIVE:To compare the psychiatric service utilization between patients who only received long-acting injectable antipsychotics (LAIAs) and those who only received oral antipsychotics (OAPs) in the maintenance treatment of chronic schizophrenia. METHODS:We constructed a cohort of chronic schizophrenia patients who underwent maintenance treatment from the Taiwan National Health Insurance Research Database in 2011 and followed these patients for 12 months. We included patients who had been diagnosed with schizophrenia for at least 3 years, were not hospitalized in 2011, and had received 1 year of maintenance treatment. Inverse probability of treatment weighting logistic, linear, and negative binomial regression models were used to estimate associated psychiatric services utilization and adjust for covariate imbalances between the LAIAs and OAPs groups. RESULTS:Among 40,194 patients, 948 (2.36%) received only LAIAs and 39,246 (97.64%) received only OAPs. Compared with those who received only OAPs, the sole LAIAs users were associated with a lower percentage of psychiatric hospitalization (8.4% and 5.8%, respectively; odds ratio: 0.63, p < .01), shorter lengths of hospitalization days (82.8 and 65.9, respectively; coefficient [b]: -16.87, p = .03), and fewer emergency room visits (2.3 and 1.8, respectively; b: -0.24, p < .01) per patient. CONCLUSIONS:Chronic schizophrenia patients who received only LAIs had a lower risk of disease relapse and a reduction in psychiatric service utilization than those receiving only OAPs.
Time to rehospitalization in patients with bipolar mania discharged on long-acting injectable or oral antipsychotics.
Lin Ching-Hua,Chan Hung-Yu,Hsu Chun-Chi,Chen Feng-Chua
Journal of affective disorders
OBJECTIVE:This study aimed to analyze time to rehospitalization in patients with bipolar mania discharged on long-acting injectable antipsychotics (LAIs) or oral antipsychotics (OAPs). Additionally, temporal trends in LAI prescription were investigated. METHODS:Patients with bipolar mania discharged from the study hospital on antipsychotics between 2006 and 2018 were included. Survival analysis was used to compare time to rehospitalization within one year of discharge between patients discharged on LAIs and OAPs, and between FGA-LAIs (first- generation antipsychotic) and SGA-LAIs (second-generation antipsychotic). The Cochrane-Armitage trend test was used to test whether a temporal trend existed for LAI prescription rates during the study period. RESULTS:The LAI group (n = 224) had a significantly lower rehospitalization rate and a significantly longer time to rehospitalization than the OAP group (n = 3836). Rehospitalization rate and time to rehospitalization were not significantly different between patients discharged on FGA-LAIs or SGA-LAIs. The LAI prescription rate grew significantly from 2.20% in 2006 to 11.58% in 2018 (Z = 5.5843, p < 0.0001). The prescription rate of SGA-LAIs also increased significantly (Z = 7.7141, p < 0.0001), but not the prescription rate of FGA-LAIs. LIMITATIONS:The treatment allocation is not randomized in this retrospective study. Furthermore, various clinical characteristics were unavailable in our analysis, such as symptom severity, functional impairment, and others. CONCLUSIONS:LAIs were significantly superior to OAPs in reducing rehospitalization risk. However, SGA-LAIs were comparable with FGA-LAIs in reducing rehospitalization risk. Use of LAIs increased significantly in discharged patients with bipolar disorder during the study period, especially SGA-LAIs.
Long-Acting Injectable Second-Generation/Atypical Antipsychotics for the Management of Bipolar Disorder: A Systematic Review.
Keramatian Kamyar,Chakrabarty Trisha,Yatham Lakshmi N
BACKGROUND:Non-adherence to medications is a major determinant of poor outcome in bipolar disorder. Second-generation long-acting injectable (LAI) antipsychotics help ensure medication adherence which in turn can lead to more favourable outcomes. However, the role of these medications in bipolar disorder is not well established. OBJECTIVE:We sought to review available evidence relating to the efficacy and safety of using second-generation LAI antipsychotics in bipolar disorder. METHODS:PRISMA guidelines were followed to systematically review all clinical studies that reported on the efficacy and safety of second-generation LAI antipsychotics in patients with bipolar disorder. We searched Ovid Medline, PsycINFO, and Cochrane Central Register of Controlled Trials from inception to November 2018. RESULTS:Of 459 identified citations, 53 studies were fully evaluated and 37 met our inclusion criteria. Overall, second-generation LAI antipsychotics were found to be well tolerated and effective for treatment of manic symptoms and preventing mood recurrences in adults with bipolar disorder. However, we found disparity in the evidence available for individual agents. While several randomized controlled trials (RCTs) reported on the use of risperidone LAI in bipolar disorder, we found only one RCT on the use of aripiprazole LAI, and none for use of paliperidone palmitate or olanzapine pamoate (evidence for the former is limited to one observational study and one case series, and for the latter to a single case report). Studies in children and adolescents were restricted to case reports and small open-label studies. CONCLUSION:Second-generation LAI antipsychotics, particularly risperidone and aripiprazole LAI, may be a safe and effective alternative to oral medications in the management of bipolar disorder.
Comparative effectiveness of long-acting injectable risperidone vs. long-acting injectable first-generation antipsychotics in bipolar disorder.
Wu Chi-Shin,Hsieh Ming H,Tang Chao-Hsiun,Chang Ching-Jui
Journal of affective disorders
OBJECTIVE:The aim of this study was to compare the treatment effectiveness between long-acting injectable risperidone and long-acting injectable first-generation antipsychotics among patients with bipolar disorder. METHOD:We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database. Patients with bipolar disorder aged 15 years or higher, who were newly administered long-acting injectable antipsychotics between June 1, 2004 and December 31, 2011 were included. The clinical outcome indexes were hospitalization for any mood, manic/mixed, or depressive episodes. In addition, the all-cause discontinuation of long-acting injectable antipsychotic treatment was also assessed. RESULTS:A total of 3916 patients with bipolar disorder were extracted. Compared with risperidone, the use of first-generation antipsychotics was associated with a higher rate of hospitalization for any mood episode and major depressive episode. However, there was no statistically significant difference in treatment discontinuation rate between risperidone and first-generation antipsychotics. LIMITATIONS:Information for the severity of mood symptoms, social support, life style, neurological and metabolic adverse effect was not available in this database. In addition, we only measured severe mood episodes with hospitalization as our outcome index. It may not be possible to generalize our findings to mild mood episodes. CONCLUSIONS:Our findings suggested that patients treated with long-acting injectable risperidone might be superior to first-generation antipsychotics in the rate of psychiatric hospitalization.
Long-acting injectable antipsychotics (LAIs) for maintenance treatment of bipolar and schizoaffective disorders: A systematic review.
Pacchiarotti Isabella,Tiihonen Jari,Kotzalidis Georgios D,Verdolini Norma,Murru Andrea,Goikolea José Manuel,Valentí Marc,Aedo Alberto,Vieta Eduard
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Long-Acting Injectable Antipsychotics (LAIs) are used to overcome non-compliance in psychoses, mainly schizophrenia spectrum disorders. We aimed to summarize available evidence of studies comparing the efficacy of LAIs to placebo or oral medications for Bipolar Disorder (BD) and/or Schizoaffective Disorder (SAD). We searched six databases from inception to 28-March-2018, using the strategy: long-acting antipsychotics AND (bipolar disorder OR schizoaffective disorder OR mania OR manic OR bipolar depression). We included peer-reviewed double-blind comparisons of LAIs for any clinical outcome occurrence in BD, or open mirror studies with same prospective as retrospective assessment periods. We excluded studies reporting on mixed schizophrenia/SAD populations without reporting results separately. The pooled records amounted to 642. After duplicate removal and inclusion/exclusion criteria application, we included 15 studies, 6 double-blind and 9 open, 13 assessing BD and 2 SAD. Depot neuroleptics prevented manic, but not depressive recurrences and may worsen depressive symptoms. Risperidone long-acting injectable was found to be effective in protecting from any mood/manic symptom compared to placebo, but not from depressive recurrences. Add-on or monotherapy paliperidone palmitate in SAD patients protected from psychotic, depressive, and manic symptoms. In patients with BD-I with a manic episode at study enrolment, aripiprazole monohydrate significantly delayed time to recurrence of manic episodes without inducing depressive episodes. LAIs are effective and well-tolerated maintenance treatments for BD and SAD. They showed better efficacy in preventing mania than depression. LAIs may be first-line for BD-I and SAD patients with a manic predominant polarity and with non-adherence problems.
Trend survey on adverse event profiles of antipsychotic long-acting injections and oral agents using the Japanese adverse drug event report database.
Hatano Masakazu,Kamei Hiroyuki,Shimato Akane,Yamada Shigeki,Iwata Nakao
This study aims to assess the differences in adverse event profiles of long-acting injectable antipsychotics (LAIs) and oral antipsychotics (OAPs) using real-world data in the Japanese Adverse Drug Event Report database. Reporting odds ratios were determined using disproportionality analysis to estimate the risk of adverse events for LAIs and OAPs. Differences in adverse event profiles between formulations were determined after propensity score matching. Time-to-onset of adverse events was compared between LAIs and OAPs using the Weibull shape parameter. Signals were detected for approximately 50% of the adverse events (12 of 22) with LAIs and for the majority of adverse events (19 of 22) with OAPs. LAIs was associated with significantly lower reporting rate than OAPs for extrapyramidal symptom, neuroleptic malignant syndrome, and dystonia. For QT prolongation, convulsions, and hyperglycemia associated with LAIs, the 95% Confidence Interval of β included 1 in time-to-onset analysis. Real-world data suggest that LAIs tend to reduce the occurrence of extrapyramidal symptom and neuroleptic malignant syndrome, but a number of other adverse events have potential risks as well as OAPs. In addition, onset of adverse events with LAIs have been shown to be slightly delayed, requiring more careful long-term monitoring.
Time to Rehospitalization in Patients With Schizophrenia Receiving Long-Acting Injectable Antipsychotics or Oral Antipsychotics.
Lin Ching-Hua,Chen Feng-Chua,Chan Hung-Yu,Hsu Chun-Chi
The international journal of neuropsychopharmacology
BACKGROUND:This study aimed to investigate and compare time to rehospitalization in patients with schizophrenia receiving long-acting injectable antipsychotics (LAIs) after discharge with those receiving oral antipsychotics. Additionally, the trend of LAIs prescription rates was investigated. METHODS:Patients with schizophrenia (n = 13 087), who were discharged from the study hospital from 2006 to 2017, were followed-up under naturalistic conditions in the year after discharge. The primary outcome was time to rehospitalization. Survival analysis was used in the comparisons between LAIs and oral antipsychotics and between FGA-LAIs and SGA-LAIs. Simple linear regression and Cochrane-Armitage trend test were used to test whether a time trend existed for LAIs prescription rates. RESULTS:In the 1 year following discharge, patients in the LAIs group had a significantly lower rehospitalization rate and a significantly lengthened time to rehospitalization than those in the oral antipsychotics group. Rehospitalization rate and time to rehospitalization were not significantly different in patients receiving FGA-LAIs or SGA-LAIs. A significantly higher percentage of patients treated with FGA-LAIs received anticholinergic agents than those treated with SGA-LAIs. The LAIs prescription rate grew significantly from 2006 to 2017 by an average of 0.5% per year. CONCLUSIONS:LAIs were significantly superior to oral antipsychotics in reducing rehospitalization risk, whereas SGA-LAIs were comparable with FGA-LAIs in reducing rehospitalization risk. However, use of concomitant anticholinergic agents was less frequent in the SGA-LAIs group than in the FGA-LAIs group. Increase in LAIs prescription rate may be due to growing experiences and success among clinicians in treating patients with LAIs.
Comparative effectiveness of second generation long-acting injectable antipsychotics based on nationwide database research in Hungary.
Takács P,Czobor P,Fehér L,Gimesi-Országh J,Fadgyas-Freyler P,Bacskai M,Rakonczai P,Borsi A,Hegyi R,Németh T,Sermon J,Bitter I
BACKGROUND:Schizophrenia is a severe condition that affects approximately 1% of the population. Certain elements of antipsychotic treatment can only be examined in large population, thus the need for population-based real-world analyses has been increasing. PATIENTS AND METHODS:Hungarian National Health Fund database includes all healthcare data of the population of Hungary. All patients diagnosed with schizophrenia between 01.01.2006 and 31.12.2015 were included in the study. We analyzed all patients with newly initiated second-generation antipsychotic during the inclusion period (01.01.2012-31.12.2013). Patients were followed for 2 years. All-cause treatment discontinuation served as the primary outcome of the study. Patients with newly initiated long-acting injectable treatments were further investigated in stratified analyses based on their previous treatment. RESULTS:106,624 patients had schizophrenia diagnosis during the study period. 12,232 patients met the inclusion criteria for newly initiating second-generation antipsychotic during the inclusion period. The proportion of patients still on treatment after 1 year for oral treatments varied between 17% (oral risperidone) and 31% (oral olanzapine) while the analogous data for long acting injectables were between 32% (risperidone long acting) and 64% (paliperidone long acting one monthly). The 2-year data were similarly in favor of long-actings. Median time to discontinuation in the oral group varied between 57 days (clozapine) and 121 days (olanzapine). The median time to discontinuation for long-actings was significantly longer: between 176 and 287 days; in case of paliperidone long acting, median was not reached during the observation period. Patients receiving long-acting treatment switched from another long-acting remained on the newly initiated treatment significantly longer than those switched from orals. CONCLUSION:Our results indicate the superiority of second generation long-acting antipsychotics with regard to rates of treatment discontinuation and periods of persistence to the assigned medication.
Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies.
Kishimoto Taishiro,Hagi Katsuhiko,Kurokawa Shunya,Kane John M,Correll Christoph U
The lancet. Psychiatry
BACKGROUND:Evidence of comparative benefits of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics for schizophrenia has been inconsistent across study designs. The aim of this study was to evaluate the comparative benefits of LAIs versus oral antipsychotics in three study designs to inform clinical decision making. METHODS:We did a comprehensive systematic review and meta-analysis comparing LAIs versus oral antipsychotics for schizophrenia covering three study designs: randomised controlled trials (RCTs), cohort studies, and pre-post studies. Our literature search was without language restrictions, in MEDLINE and PubMed, the Cochrane Library, Scopus, and Embase, for studies published from database inception up to a last search on March 13, 2020. We also searched for unpublished studies and ClinicalTrials.gov. We included studies lasting at least 6 months that targeted adults with schizophrenia and related disorders (>80% of participants). Studies on penfluridol (neither an LAI or daily oral antipsychotic), case reports, and case series with fewer than 20 patients were excluded. Two investigators independently extracted study-level data and resolved disagreement by consensus, or via a third investigator. Study authors were contacted to obtain additional information as needed. For our primary outcome we meta-analysed the risk ratio (RR) for hospitalisation or relapse with LAIs versus oral antipsychotics by a random-effects model, with hospitalisation used preferentially over relapse. As secondary analyses, we reversed the preferential order to relapse over hospitalisation, and assessed hospitalisation risk and relapse risk individually. Other secondary outcomes included all meta-analysable data, classed by relevance to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, and analysed by study design. Dichotomous outcomes were expressed as pooled RR and continuous outcomes as standardised mean difference (SMD). The protocol is registered with PROSPERO (CRD42019142094). FINDINGS:We identified 14 687 records, of which 137 studies (397 319 patients) met the inclusion criteria (32 RCTs [23·4%; 8577 patients], 65 cohort studies [47·4%; 377 447 patients], and 40 pre-post studies [29·2%; 11 295 patients]) and were analysed. The quality of studies in terms of risk of bias varied across study designs and within each study design from low to high. LAIs were associated with a lower risk of hospitalisation or relapse than oral antipsychotics in each of the three study designs (RCTs: 29 studies, 7833 patients, RR 0·88 [95% CI 0·79-0·99], p=0·033; cohort studies: 44 studies, 106 136 patients, RR 0·92 [0·88-0·98], p=0·0044; pre-post studies: 28 studies, 17 876 patients, RR 0·44 [0·39-0·51], p<0·0001). This association was maintained across the study designs when we reversed the preferential order to risk of relapse over hospitalisation, and in individual analysis of hospitalisation risk. The association was maintained only in pre-post studies for relapse risk alone. In all other outcomes related to effectiveness, efficacy, safety, quality of life, cognitive function, and other outcomes, LAIs were more beneficial than oral antipsychotics in 60 (18·3%) of 328 comparisons, not different in 252 (76·8%) comparisons, and less beneficial in 16 (4·9%) comparisons when analysed by study design. Significant heterogeneity was observed across all three study designs. Publication biases were apparent in cohort and pre-post studies, but effect sizes were similar after trim-and-fill analyses. INTERPRETATION:Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre-post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia. FUNDING:None. TRANSLATIONS:For the Chinese, French, German, Italian, Japanese, Portugese and Spanish translations of the abstract see Supplementary Materials section.
Continuation of schizophrenia treatment with three long-acting injectable antipsychotics in South Korea: A nationwide population-based study.
Joo Sung Woo,Shon Seung-Hyun,Choi GumJee,Koh MinJung,Cho Seung Woo,Lee Jungsun
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Long-acting injectable (LAI) antipsychotics have been developed to prevent symptom relapse in patients with schizophrenia; relapse has a detrimental clinical impact and high social burden. However, data on treatment continuation rates of LAI antipsychotics are inconsistent, primarily because of study design; limited data exist for patients taking oral psychotropic medications taken along with LAI antipsychotics, and factors related to LAI antipsychotics treatment discontinuation. Patients with schizophrenia in the South Korea Health Insurance Review Agency database from 2007 to 2016 who had received LAI haloperidol, LAI paliperidone, or LAI risperidone were included. Treatment continuation rates and proportions of patients using concurrent oral psychotropic medications were calculated. Cox proportional hazard ratios were used for analysis related to discontinuation. There was a significant difference in treatment continuation rates at 6 months after initiation (36.8% LAI haloperidol, 57.5% LAI paliperidone, and 34.5% LAI risperidone). A substantial proportion of patients in all three groups were prescribed oral antipsychotics during LAI antipsychotics treatment. In the LAI paliperidone group, type of hospital was significantly associated with a higher risk of treatment discontinuation, with a hazard ratio of 1.195-1.598. Early discontinuation of LAI antipsychotic treatment occurs in a large number of patients with schizophrenia. Intervention strategies for improving the LAI antipsychotics treatment adherence are needed.
Risk of discontinuation of antipsychotic long-acting injections vs. oral antipsychotics in real-life prescribing practice: a community-based study.
Verdoux H,Pambrun E,Tournier M,Bezin J,Pariente A
Acta psychiatrica Scandinavica
OBJECTIVE:To compare the risk of discontinuation of ambulatory antipsychotic treatment in persons treated with antipsychotic long-acting injections (LAIs) or by oral antipsychotics (OAPs). METHODS:The study was performed in a representative sample of persons newly treated with OAPs (n = 6904) affiliated to the French Insurance Healthcare system. The risk of all-cause discontinuation was compared in patients prescribed OAPs (n = 246) vs. matched patients prescribed LAIs (n = 246) using multivariate survival analyses. Confounding by indication was minimized by matching on type of antipsychotic drug and by the high-dimensional propensity score method. RESULTS:Discontinuation was more frequent with OAPs (69%) compared to LAIs (57%) [adjusted relative risk (aRR) = 1.6, 95% CI 1.23-2.07]. Risk of discontinuation was higher for first-generation (FGA) OAPs vs. FGA LAIs (aRR = 1.94, 95% CI 1.22-3.08) as well as for second-generation (SGA) OAPs vs. SGA LAIs (aRR = 1.58, 95% CI 1.15-2.17). Over the 6-month period after discontinuation of LAIs, a new antipsychotic drug was dispensed in 58% of patients, the most frequent pattern being dispensing of the same LAI as that prescribed before discontinuation. CONCLUSIONS:Although less frequent than with OAPs, the rate of ambulatory treatment discontinuation was high with LAIs. Prescription of LAIs should be associated with intervention strategies aimed at promoting medication adherence.
Antipsychotic Adherence and Rehospitalization in Schizophrenia Patients Receiving Oral Versus Long-Acting Injectable Antipsychotics Following Hospital Discharge.
Marcus Steven C,Zummo Jacqueline,Pettit Amy R,Stoddard Jeffrey,Doshi Jalpa A
Journal of managed care & specialty pharmacy
BACKGROUND: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. OBJECTIVE: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. METHODS: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). RESULTS: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). CONCLUSIONS: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.
Hyperprolactinemia in psychotic patients treated in monotherapy with long-acting injectable antipsychotics.
Bonete Llácer José María,Martínez Hortelano Alicia,Richart Albelda Begoña
International journal of psychiatry in clinical practice
Hyperprolactinemia (HPRL), defined as plasma prolactin (PRL) >25 ng/ml, is a frequent adverse effect of the treatment with some antipsychotics. The objectives of this study were to determine the prevalence of HPRL among schizophrenic patients treated with long-acting injectable (LAI) antipsychotic drugs at our hospital, and to estimate gender effects in PRL levels in these patients. This cross-sectional, retrospective, study analyzed 165 psychotic patients treatment with LAI antipsychotics in monotherapy from February to May of 2017 at the Psychiatry Specialized Care Units of the Elche General Hospital (Spain). The prevalence of antipsychotic-derived HPRL in our hospital was 52.41%. Patients treated with LAI formulations of paliperidone and risperidone presented the highest levels of HPRL. A linear regression model showed that female patients presented 24.95 ng/ml (CI95 = 16.85, 33.05) higher levels of PRL than male patients ( < .0001). For women, age >45 years was associated to reduced levels of PRL with respect to younger patients (mean= -18.86 ng/ml, CI95 = -35.59, -2.13, < .05). Our study confirmed the effects of LAI paliperidone and risperidone on PRL levels. Sex and age were significantly associated with PRL levels in patients treated with LAI antipsychotics, with younger women presenting higher rates of HPRL than men. Key points HPRL is a common adverse effect of the treatment with antipsychotics, detectable in over half of the patients treated in our hospital. Our study showed that treatment with LAI formulations of paliperidone and risperidone resulted in the highest levels of HPRL. Sex and age were significantly associated with PRL levels in patients treated with LAI antipsychotic drugs, with younger women presenting higher rates of HPRL than men.
Attitudes of European physicians towards the use of long-acting injectable antipsychotics.
Patel Maxine X,Bent-Ennakhil Nawal,Sapin Christophe,di Nicola Sylvie,Loze Jean-Yves,Nylander Anna-Greta,Heres Stephan
BACKGROUND:Prescription rates for long-acting injectable (LAI) antipsychotic formulations remain relatively low in Europe despite improved adherence over alternative oral antipsychotic treatments. This apparent under-prescription of LAI antipsychotics may have multiple contributing factors, including negative mental health practitioner attitudes towards the use of LAIs. METHODS:The Antipsychotic Long acTing injection in schizOphrenia (ALTO) non-interventional study (NIS), conducted across several European countries, utilised a questionnaire that was specifically designed to address physicians' attitudes and beliefs towards the treatment of schizophrenia with LAI antipsychotics. Exploratory principal component analysis (PCA) of feedback from the questionnaire aimed to identify and characterize the factors that best explained the physicians' attitudes towards prescription of LAIs. RESULTS:Overall, 136/234 solicited physicians returned fully completed questionnaires. Physicians' mean age was 48.5 years, with mean psychiatric experience of 20.0 years; 69.9% were male, 84.6% held a consultant position, and 91.9% had a clinical specialty in general adult care. Most physicians considered themselves to have a high level of clinical experience with LAI antipsychotics (77.2%), with an increased rate of LAI antipsychotics prescription over the last 5 years (59.6%). Although the majority of physicians (69.9%) declared feeling no difference in stress levels when offering LAI compared to oral antipsychotics, feelings of 'no/more stress' versus 'less stress' was found to influence prescription patterns. PCA identified six factors which collectively explained 66.1% of the variance in physician feedback. Multivariate analysis identified a positive correlation between physicians willing to accept usage of LAI antipsychotics and the positive attitude of colleagues (co-efficient 3.67; p = 0.016). CONCLUSIONS:The physician questionnaire in the ALTO study is the first to evaluate the attitudes around LAI antipsychotics across several European countries, on a larger scale. Findings from this study offer an important insight into how physician attitudes can influence the acceptance and usage of LAI antipsychotics to treat patients with schizophrenia.
Long-acting atypical antipsychotics in schizophrenia: A systematic review and meta-analyses of effects on functional outcome.
Olagunju Andrew T,Clark Scott R,Baune Bernhard T
The Australian and New Zealand journal of psychiatry
OBJECTIVE:Impairment in psychosocial function is common in schizophrenia. Long-acting injectable atypical antipsychotics are thought to enhance psychosocial function by boosting adherence. However, no systematic review has examined the effects of long-acting injectable atypical antipsychotics on psychosocial function in clinical trials. METHODS:We searched major databases including Medline/PubMed, PsychINFO, EMBASE, CINAHL, Scopus, Web of Science, Cochrane Central Register of Controlled Trials and Clinical Trial Registries for randomised controlled trials that compared long-acting injectable atypical antipsychotics to placebo, oral antipsychotic medications or long-acting injectable atypical antipsychotics for all years till 2018, with no language limits. We performed a systematic review of findings on change in psychosocial function and its predictors in the included reports. Data on change in psychosocial functioning were meta-analysed using a random-effects model. RESULTS:A total of 26 studies were included in systematic review, and 19 studies with 8616 adults, 68.1% males were meta-analysed. Long-acting injectable atypical antipsychotics were superior to placebo (standardised mean difference = 0.39; 95% confidence interval = [0.32, 0.47]; p < 0.001; I = 0%; 9 studies) and oral antipsychotic medications (standardised mean difference = 0.16; 95% confidence interval = [0.01, 0.31]; p = 0.04; I = 77%; 10 studies) for improved psychosocial function and superiority was maintained in short- and long trials. Poor psychosocial function was predicted by longer treatment duration, severe symptoms, poor cognition and poor insight. Functioning was assessed by either a single or a combination of measures, but was not the primary outcome in most studies. Other sources of bias include poor blinding and reporting of randomisation. CONCLUSION:Long-acting injectable atypical antipsychotics are beneficial for recovery of psychosocial function in comparison with placebo, but the magnitude of superiority over oral antipsychotic treatment was small. Severe psychopathology at baseline predicted poor psychosocial function. Future effectiveness trials in which post-randomisation involvement is kept to a minimum, and psychosocial function is included as primary outcome a priori, are needed to capture the real-world impact of long-acting injectable atypical antipsychotics and to address methodological biases.
Prevalence of concomitant oral antipsychotic drug use among patients treated with long-acting, intramuscular, antipsychotic medications.
Aggarwal Neil Krishan,Sernyak Michael J,Rosenheck Robert A
Journal of clinical psychopharmacology
OBJECTIVE:Long-acting injectable (LAI) antipsychotic drugs are viewed as monotherapeutic alternatives to oral medications to promote medication adherence, but there have been no descriptive studies of concomitant use of oral and LAI medications. METHODS:A list of all patients receiving services from the Connecticut Mental Health Center from July 1, 2009, to June 30, 2010, was obtained from center administrative records, and those carrying an initial intake diagnosis of schizophrenia or schizoaffective disorder were identified. All team leaders were approached, and all clinicians were asked to identify patients on their case load prescribed LAIs during the time interval above. Also, all internal and external pharmacy orders were reviewed. Concomitancy was defined as simultaneous oral and LAI antipsychotic use at any time from July 1, 2009, to June 30, 2010. Data were culled from the medical records using a form (available on request) that recorded current LAI antipsychotic, reasons for LAI use, length of time on LAI, monthly dosage, and all concomitant oral antipsychotics, antidepressants, and anxiolytic agents. RESULTS:Among 124 patients on LAI medications, 57 (46%) received concomitant oral and LAI antipsychotics: 27 (47%) were prescribed LAI haloperidol, 19 (33%) LAI fluphenazine, and 11 (19%) risperidone microspheres. Logistic regression showed greater use of oral antipsychotic for both Hispanic ethnicity (odds ratio, 3.8; 95% confidence interval, 1.3-10.8) and alcohol abuse/dependence (odds ratio, 6.5; 95% confidence interval, 1.3-31.9), with no significant differences on other variables. There were no significant differences between LAI agents in rates of use of concomitant oral antipsychotic, anticholinergic, sedative/hypnotic, or mood stabilizer. Patients were more likely to be prescribed concomitant oral preparations of their LAI agent than another oral antipsychotic. Higher dosing of LAI treatments was associated with a significantly greater likelihood of use of oral psychotropics and anticholinergics. CONCLUSIONS:Almost one half of patients prescribed LAI antipsychotics receive oral antipsychotics and other oral psychotropics. This challenges the notion that LAIs are used as monotherapy in real-world settings. Concomitant oral and LAI antipsychotic prescriptions may represent a common practice of polypharmacy that merits further investigation.
Long-acting injectable antipsychotics and the development of postinjection delirium/sedation syndrome (PDSS).
Novakovic Vladan,Adel Tymaz,Peselow Eric,Lindenmayer Jean-Pierre
OBJECTIVES: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. METHODS: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. RESULTS: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). CONCLUSIONS: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.
Long-acting injectable antipsychotics update: lengthening the dosing interval and expanding the diagnostic indications.
Expert review of neurotherapeutics
INTRODUCTION: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.
Long-acting injectable antipsychotics: evidence of effectiveness and use.
Manchanda Rahul,Chue Pierre,Malla Ashok,Tibbo Phil,Roy Marc-André,Williams Richard,Iyer Srividya,Lutgens Danyael,Banks Nicola
Canadian journal of psychiatry. Revue canadienne de psychiatrie
OBJECTIVE:To review the evidence for the role of long-acting injectable (LAI) antipsychotics (APs), especially the second-generation AP (SGA) LAIs, in the treatment of schizophrenia and to discuss the use rates of LAIs in Canada. METHOD:A search of online medical databases was conducted of the published literature (1995-2012) of the effects of LAIs on the domains of remission, adherence, relapse, and hospitalization. Results obtained from randomized controlled trials (RCTs), systematic reviews, meta-analyses, and large-scale observational studies were included. Expert consensus data were also solicited on LAI use within a Canadian context. RESULTS:While the efficacy of LAIs, compared with placebo, is well established, the evidence from RCTs is equivocal for any specific advantage for SGA LAIs, compared with oral medications, probably owing to challenges in conducting such RCTs. Evidence from methodologically less rigorous studies and from clinical practice suggests some advantages in achieving and maintaining remission, risk of relapse, and hospitalization. The rate of LAI (first-generation AP and SGA) use from published outpatient studies is low at 6.3% in Canada, compared with 15% to 80% worldwide. However, there is a relatively high rate of use in specific early psychosis programs and in conjunction with community treatment orders in Canada. CONCLUSIONS:LAIs are at least as effective as oral APs in the treatment of psychotic disorders. The former may have specific advantages for patients who demonstrate covert nonadherence. The underuse of LAIs in Canada needs to be better understood and addressed.
Plasma Levels of Long-Acting Injectable Antipsychotics in Outpatient Care: A Retrospective Analysis.
Hýža Martin,Šilhán Petr,Češková Eva,Skřont Tomáš,Kacířová Ivana,Uřinovská Romana,Grundmann Milan
Neuropsychiatric disease and treatment
Purpose:Antipsychotic efficacy in schizophrenia depends on its availability in the body. Although therapeutic outcomes remain still far from satisfactory, therapeutic drug monitoring is not a common part of clinical practice during treatment with long-acting injectable antipsychotics (LAI AP). The real effectiveness of LAI AP is thus uncertain. Patients and Methods:We made a retrospective evaluation of plasma levels of LAI AP. Collection of blood samples was performed just before the drug application and one week later. Forty patients with a stabilized clinical condition and steady-state plasma levels were included. Results:In the observed cohort of patients, flupentixol decanoate (n = 23) was the most often used drug, followed by fluphenazine decanoate (n = 7), haloperidol decanoate (n = 5), paliperidone palmitate (n = 3), and risperidone microspheres (n = 2). Just 5 of 40 patients were treated with a monotherapy. In the period before the application, 60% of the patients did not reach the therapeutic reference range (TRR) and 20% of the patients had an undetectable plasma level. At the time of collection of the second blood samples performed after 7 days, 24% of the patients were under the TRR. Conclusion:We have found a surprisingly high incidence of plasma levels under the TRR in patients treated with LAI AP. Notwithstanding individual variability in pharmacokinetics, it seems that LAI AP may be underdosed in usual clinical practice.
Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia.
Park Eun Ji,Amatya Sarmila,Kim Myung Sun,Park Jong Hoon,Seol Eunyoung,Lee Heeyong,Shin Young-Hee,Na Dong Hee
Archives of pharmacal research
Antipsychotic drugs have been used to treat patients with schizophrenia and other psychotic disorders. Long-acting injectable antipsychotic drugs are useful for improving medication compliance with a better therapeutic option to treat patients who lack insight or adhere poorly to oral medication. Several long-acting injectable antipsychotic drugs are clinically available. Haloperidol decanoate and fluphenazine decanoate are first-generation depot drugs, but the use of these medicines has declined since the advent of second-generation depot agents, such as long-acting risperidone, paliperidone palmitate, and olanzapine pamoate. The second-generation depot drugs are better tolerated and have fewer adverse neurological side effects. Long-acting injectable risperidone, the first depot formulation of an atypical antipsychotic drug, was prepared by encapsulating risperidone into biodegradable microspheres. Paliperidone palmitate is an aqueous suspension of nanocrystal molecules, and olanzapine pamoate is a microcrystalline salt of olanzapine and pamoic acid suspended in aqueous solution. This review summarizes the characteristics and recent research of formulations of each long-acting injectable antipsychotic drug.
A Systemic Review and Experts' Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder.
Chou Yuan Hwa,Chu Po-Chung,Wu Szu-Wei,Lee Jen-Chin,Lee Yi-Hsuan,Sun I-Wen,Chang Chen-Lin,Huang Chien-Liang,Liu I-Chao,Tsai Chia-Fen,Yen Yung-Chieh
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology
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.
Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview.
Correll Christoph U,Kim Edward,Sliwa Jennifer Kern,Hamm Wayne,Gopal Srihari,Mathews Maju,Venkatasubramanian Raja,Saklad Stephen R
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.
Extent of use of long-acting injectable antipsychotics in children and adolescents within Indiana Medicaid.
Modesitt Taylor,Kubascik Erica,Ott Carol
The mental health clinician
Introduction:Oral formulations of the antipsychotics aripiprazole, asenapine, lurasidone, olanzapine, paliperidone, quetiapine, and risperidone are indicated for use in pediatrics for several diagnoses. Long-acting injectable (LAI) antipsychotics are of interest in this special population because they may be used due to convenience and desire to improve adherence, despite limited support in the literature. The primary intent of this study is to provide descriptive information on the use of paliperidone palmitate, risperidone microspheres, aripiprazole extended-release injection, and olanzapine pamoate in pediatric patients within Indiana Medicaid. Methods:This study was a retrospective database analysis, which retrieved information from Indiana Medicaid over a 2-year timeframe spanning from July 1, 2012, through June 30, 2014. The study included the prescription medications filled for all children and adolescents within Indiana Medicaid who received the LAI antipsychotics paliperidone palmitate, risperidone microspheres, aripiprazole extended-release injection, and olanzapine pamoate. Results:From July 1, 2012, through June 30, 2014, 150 Indiana Medicaid patients younger than 18 years old were prescribed a LAI atypical antipsychotic. A total of 1013 LAI atypical antipsychotic doses were billed to Indiana Medicaid during the study period for pediatric patients. Paliperidone palmitate was billed most frequently. Discussion:Long-acting injectable atypical antipsychotics are being prescribed for children and adolescents within Indiana Medicaid, despite minimal clinical evidence supporting use. There is a need for further research in this area to increase generalizability of results and aid in implementation of policies to prevent inappropriate use of LAI antipsychotics in children and adolescents.
Risperidone long-acting injection.
Expert review of neurotherapeutics
Risperidone long-acting is the first atypical antipsychotic medication available in an injectable sustained-action formulation, potentially conferring the advantages of an atypical antipsychotic together with assured medication delivery. In addition, unlike depots of conventional antipsychotics composed of a prodrug in a viscous oil vehicle, this formulation uses microsphere technology to encapsulate risperidone in a biodegradable polymer. Progressive hydrolysis of the microspheres results in gradual release of risperidone leading to predictable and sustained plasma levels with repeated injections.
Long-acting injectable antipsychotics: what, when, and how.
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.
Risks versus benefits of different types of long-acting injectable antipsychotics.
McEvoy Joseph P
The Journal of clinical psychiatry
Since their introduction into clinical practice in the early 1960s, long-acting depot antipsychotics have been widely used as maintenance therapy for patients with schizophrenia. The improved pharmacokinetics of injectable long-acting antipsychotic therapies have provided more reliable drug delivery and reduced differences in peak and trough plasma levels of the drug. Studies that have compared short-acting oral antipsychotics with long-acting injectable antipsychotics, although imperfect, support injectable antipsychotics as having real benefit over oral antipsychotics on patient outcome owing largely to improved adherence. If patients forget or refuse to take their prescribed oral medications, weeks or months may go by before they experience an exacerbation; the effects of nonadherence become apparent too late to preempt the problem. On the other hand, if a patient fails to show up for an injection, the problem of nonadherence can be immediately addressed. When injectable medication is combined with an active psychosocial treatment program that will respond assertively to nonadherence, relapse rates may be reduced. By preventing or delaying relapse, consistent treatment can improve the patient's quality of life and lead to an overall reduction in the cost of care.
Effects of cabergoline on hyperprolactinemia, psychopathology, and sexual functioning in schizophrenic patients.
Kalkavoura Christina S,Michopoulos Ioannis,Arvanitakis Periklis,Theodoropoulou Pitsa,Dimopoulou Konstantina,Tzebelikos Errikos,Lykouras Lefteris
Experimental and clinical psychopharmacology
Antipsychotic medications are associated to different degrees with sexual dysfunction mainly through their potential to induce hyperprolactinemia. Prolactin (PRL) secretion is mainly regulated by the hypothalamic dopaminergic systems. We conducted this 6-month, parallel-group study to prospectively investigate the effects of the dopamine agonist cabergoline on sexual dysfunction in clinically stable patients with schizophrenia (DSM-IV, AP 194) and hyperprolactinemia (PRL > 20 ng/ml for men and PRL > 25 ng/ml for women). In total 80 patients were enrolled; 33 were receiving risperidone, 17 haloperidol, 11 amisulpride, and 8 risperidone microspheres long acting. Based on PRL levels (< 50, 50-99, or > 100 ng/ml), patients were assigned in 3 cabergoline doses (0.25, 0.5, and 1 mg/day in 38, 23, and 19 patients, respectively). The psychopathology was evaluated using the Positive and Negative Syndrom Scale (PANSS), and sexual dysfunction was evaluated using the Arizona Sexual Experiences Scale (ASEX). PRL levels were reduced in all patients, from 73.3 (± 46.8) to 42.0 (± 27.8) at Month 3 and 27.1 (± 20.4) at Month 6 (p < .001). ASEX scores declined from 19.1 (± 5.1) to 17.6 (± 5.5) at Month 3 and 15.0 (± 6.5) at Month 6 (p < .001). PANSS scores were reduced in the third and in the sixth month (p = .001 at 6 month vs. baseline). The decrease in PRL was not statistically different between groups. Our data suggest that cabergoline administration to clinically stable patients with schizophrenia may improve sexual functioning without adversely affecting their psychopathologic status, provided that the dose has been suited to the severity of the hyperprolactinemia.
Dosing patterns in Europe: Efficacy and safety of risperidone long-acting injectable in doses of 25, 37.5 and 50 mg.
Mauri Massimo Carlo,Turner Martin,Volonteri Lucia S,Medori Rossella,Maier Wolfgang
International journal of psychiatry in clinical practice
Objective. To assess the dose prescription patterns for risperidone long-acting injectable (RLAI) in patients with schizophrenia who participated in the 6-month, open-label Switch to Risperidone Microspheres (StoRMi) trial. Methods. Clinically stable patients requiring a change in medication were converted to RLAI prescribed using clinically-appropriate doses, as determined by treating clinicians. RLAI 25 mg was recommended as the starting dose, although higher initiation doses were permitted if deemed necessary. RLAI was administered intramuscularly every 2 weeks, with dosage adjustments permitted, and continued for a total of 6 months. Efficacy outcomes included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Treatment-emergent adverse events (AEs) were monitored. Results. A total of 1,849 patients were included. Modal dose was 25 mg for 52.9% of patients. At baseline, patients treated with lower RLAI doses were more likely to be female, have shorter disease duration, milder symptoms, and be using less polypharmacy. The strongest predictors that a patient would remain on 25 mg RLAI were baseline PANSS hallucinatory behaviour item score (odds ratio [OR]=0.78), baseline CGI-S score (OR=0.69), female gender (OR=1.56), and country of residence (P<0.001 for all). Efficacy measures improved in all dose groups, with the greatest improvement seen in patients treated with lower doses. AEs were more common in patients treated with 50 mg RLAI (68 vs. 57% with lower doses; P<0.0001), although most AEs were mild to moderate in severity. Conclusion. In this study, 25 mg RLAI was the most commonly prescribed dose. RLAI was effective and well tolerated over the full range of doses.
Long-acting risperidone injection: efficacy, safety, and cost-effectiveness of the first long-acting atypical antipsychotic.
Neuropsychiatric disease and treatment
OBJECTIVE:To review the pharmacokinetics, efficacy, safety, and cost-effectiveness of long-acting risperidone. METHODS:Studies published between January 2000 and October 2006 evaluating the pharmacokinetics, efficacy, safety, and cost-effectiveness of long-acting risperidone were reviewed, as identified from literature searches using Medline and EMBASE. Abstracts and posters on long-acting risperidone presented at key psychiatry congresses and available in the public domain during this time period were also reviewed. RESULTS:The unique pharmacokinetic profile of long-acting risperidone is derived from the encapsulation of risperidone in a glycolide/lactide matrix in the form of microspheres such that after a single intramuscular injection, significant plasma levels of the drug are achieved after week 3. Steady state, after repeated administration at 2-week intervals, is achieved after 3 injection cycles. Short- and long-term studies have demonstrated that long-acting risperidone (25, 37.5, or 50 mg) is both efficacious and well tolerated in a wide variety of patients with schizophrenia and related psychoses. Most patients can be switched from other oral and long-acting antipsychotic agents without compromising efficacy and safety. Long-acting risperidone may also reduce overall healthcare costs by decreasing rates of relapse and hospitalization. CONCLUSION:The assured delivery of an atypical antipsychotic medication with long-acting risperidone has important implications for patient compliance, maintenance of stability, consistency of treatment, and improving patient outcomes including the achievement of remission.
Real-life persistence of long-acting injectable antipsychotics in schizophrenic patients: A retrospective observational study in France
Guillon Pascal,Harmand Sarah,Ansolabehere Xavier
International journal of clinical pharmacology and therapeutics
OBJECTIVE: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. MATERIALS AND METHODS: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). RESULTS: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. CONCLUSION: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.
Cost-effectiveness of 3-month paliperidone therapy for chronic schizophrenia in the Netherlands.
Einarson Thomas R,Bereza Basil G,Tedouri Fadi,Van Impe Kristel,Denee Tom R,Dries Pieter J T
Journal of medical economics
BACKGROUND:A new depot formulation of paliperidone has been developed that provides effective treatment for schizophrenia for 3 months (PP3M). It has been tested in phase-3 trials, but no data on its cost-effectiveness have been published. PURPOSE:To determine the cost-effectiveness of PP3M compared with once-monthly paliperidone (PP1M), haloperidol long-acting therapy (HAL-LAT), risperidone microspheres (RIS-LAT), and oral olanzapine (oral-OLZ) for treating chronic schizophrenia in The Netherlands. METHODS:A previous 1-year decision tree was adapted, based on local inputs supplemented with data from published literature. The primary analysis used DRG costs in 2016 euros from the insurer perspective, as derived from official lists. A micro-costing analysis was also conducted. For the costing scenario, official list prices were used. Clinical outcomes included relapses (treated as outpatients, requiring hospitalization, total), and quality-adjusted life-years (QALYs). Rates and utility scores were derived from the literature. Economic outcomes were the incremental cost/QALY-gained or relapse-avoided. Model robustness was examined in scenario, 1-way, and probability sensitivity analyses. RESULTS:The expected cost was lowest with PP3M (8,781€), followed by PP1M (10,325€), HAL-LAT (11,278€), RIS-LAT (11,307€), and oral-OLZ (13,556€). PP3M had the fewest total relapses/patient (0.36, 0.94, 1.39, 1.21, and 1.70, respectively), hospitalizations (0.11, 0.46, 0.40, 0.56, and 0.57, respectively), emergency room visits (0.25, 0.48. 0.99, 0.65, and 1.14, respectively) and the most QALYs (0.847, 0.735, 0.709, 0.719, and 0.656, respectively). In both cost-effectiveness and cost-utility analyses, PP3M dominated all other drugs. Sensitivity analyses confirmed base case findings. In the costing analysis, total costs were, on average, 31.9% higher than DRGs. CONCLUSIONS:PP3M dominated all commonly used drugs. It is cost-effective for treating chronic schizophrenia in the Netherlands. Results were robust over a wide range of sensitivity analyses. For patients requiring a depot medication, such as those with adherence problems, PP3M appears to be a good alternative anti-psychotic treatment.
Long-acting risperidone: a review of its use in schizophrenia.
Harrison Tracy Swainston,Goa Karen L
UNLABELLED:Long-acting risperidone (Risperdal Consta) is a novel, intramuscular formulation of the atypical antipsychotic risperidone, which has shown efficacy in the treatment of patients with schizophrenia.Long-acting risperidone is pharmacokinetically equivalent to and causes less plasma drug concentration fluctuation than the oral formulation. This novel formulation is an aqueous suspension of microspheres comprising risperidone and a biodegradable copolymer. Significant release of risperidone from the microspheres begins 3 weeks after the first injection: thus, administration of another antipsychotic is necessary during this period only. Steady-state plasma concentrations are reached after the fourth injection. Elimination is complete 7-8 weeks after the last injection.Long-acting risperidone 25 or 50mg every 2 weeks demonstrated significantly greater antipsychotic efficacy than placebo and equivalent efficacy to oral risperidone 2-6 mg/day in two randomised, double-blind, double-dummy, 12-week trials of patients with schizophrenia. Additionally, in one of these trials, improvements in health-related quality of life (HRQOL) were superior with long-acting risperidone than placebo. Compared with baseline, improvements in the symptoms of schizophrenia in stable patients were significant with long-acting risperidone 25 or 50mg (12-month trial) and 25, 37.5 or 50mg (12-week trial) every 2 weeks, in two noncomparative, multicentre trials. Patient satisfaction with their medication and patient HRQOL mental health scores improved significantly in the 12-month trial.Long-acting risperidone is generally well tolerated, with a low incidence of injection site pain and an otherwise similar profile of adverse effects to the oral formulation. The overall incidence of extrapyramidal disorders in clinical trials was low (< or= 10%) with similar, yet minimal, changes in extrapyramidal symptom severity between patients treated with long-acting risperidone, oral risperidone or placebo. Tardive dyskinesia was reported in the 12-month trial, in 0.7% of patients. CONCLUSIONS:Long-acting risperidone is effective and generally well tolerated in patients with schizophrenia, including those patients with stable symptoms. Long-acting risperidone is the first atypical antipsychotic available in a formulation which offers a sustained, steady release of drug and is thus an attractive, new option in the treatment of patients with schizophrenia.
Clinical review of a long-acting, injectable formulation of risperidone.
Knox Erin Danielle,Stimmel Glen L
BACKGROUND:A long-acting, injectable risperidone formulation is the first depot atypical antipsychotic drug to become available in the United States. OBJECTIVE:The intent of this article is to review the efficacy and safety data available for long-acting, injectable risperidone. METHODS:Information was identified via MEDLINE (years, 1990-May 2004) using the terms risperidone, long-acting injectable, depot, and delayed-action preparations. The manufacturer also provided information about risperidone in the form of abstracts and summaries of professional meetings. RESULTS:Several 12-week studies and one 12-month study suggest that long-acting risperidone is an effective and well-tolerated treatment option for the maintenance therapy of schizophrenia. Thus far, no unexpected adverse events have been reported with the long-acting formulation. Extrapyramidal symptoms with long-acting risperidone were uncommon, dose-related, and similar to those observed with oral risperidone in short-term trials. A small, dose related weight gain occurred with long acting risperidone, again similar to that seen with oral risperidone. Pain at the injection site was uncommon and decreased with continued administration. The long-acting, injectable formulation comes in an aqueous suspension of microspheres. There is no initial drug release after injection; the main release of risperidone begins at week 2 to 3 postinjection, increases during weeks 3 and 4, is maintained during weeks 4 through 6, and declines between weeks 6 and 7. With repeated injections every 2 weeks, steady-state levels are usually reached by weeks 6 to 8. For most patients, the initial dosage should be 25 mg every 2 weeks, and oral administration should continue for the first 3 weeks after initial injection. Doses can be increased every 8 weeks to a maximum of 50 mg every 2 weeks. CONCLUSION:Long-acting risperidone offers clinicians a combination of the benefits of a depot antipsychotic drug with the therapeutic advantages of an atypical antipsychotic drug.
Treatment continuation of four long-acting antipsychotic medications in the Netherlands and Belgium: A retrospective database study.
Decuypere Flore,Sermon Jan,Geerts Paul,Denee Tom R,De Vos Cedric,Malfait Bart,Lamotte Mark,Mulder Cornelis L
Achieving greater continuation of treatment is a key element to improve treatment outcomes in schizophrenia patients. However, reported treatment continuation can differ markedly depending on the study design. In a retrospective setting, treatment continuation remains overall poor among patients using antipsychotics. This study aimed to document the difference in treatment continuation between four long-acting injectable antipsychotics based on the QuintilesIMS LRx databases, national, longitudinal, panel based prescription databases of retail pharmacies, in the Netherlands and Belgium. Paliperidone palmitate once monthly, risperidone microspheres, haloperidol decanoate, and olanzapine pamoate were studied. This study demonstrated significantly higher treatment continuation of paliperidone palmitate once monthly compared to risperidone microspheres (p-value<0,01) and haloperidol decanoate (p-value<0,01) in both countries, a significantly higher treatment continuation of paliperidone palmitate once monthly compared to olanzapine pamoate in the Netherlands (p-value<0,01), and a general trend towards better treatment continuation versus olanzapine pamoate in Belgium. Analysing the subgroup of patients without previous exposure to long-acting antipsychotic treatment revealed the positive impact of previous exposure on treatment continuation with a subsequent long acting treatment. Additionally, the probability of restarting the index therapy was higher among patients treated with paliperidone palmitate once monthly compared to patients treated with risperidone microspheres and haloperidol decanoate. The data source used and the methodology defined ensured for the first time a comparison of treatment continuation in a non-interventional study design for the four long-acting injectable antipsychotics studied.
Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies.
Möller Hans-Jürgen,Llorca Pierre-Michel,Sacchetti Emilio,Martin Stephen D,Medori Rossella,Parellada Eduard,
International clinical psychopharmacology
The maintained antipsychotic efficacy of risperidone long-acting injectable (RLAI) was investigated in patients with schizophrenia or other psychoses who were transitioned directly from their previous antipsychotic medication. Patients symptomatically stable, but considered to require a treatment change, received 25 mg of RLAI (increased to 37.5 or 50 mg, if necessary) every 2 weeks for 6 months. Assessments included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), SF-36 Health-Related Quality of Life Questionnaire and Extrapyramidal Symptoms Rating Scale (ESRS). Of 1876 patients enrolled, 74% completed the 6-month study. The most frequent reasons for treatment change were non-compliance (38%), insufficient efficacy (33%) and side-effects (26%). There was a significant reduction from baseline to endpoint in mean total PANSS score and in the scores on all PANSS subscales and symptom factors (P<0.001). CGI-S improved significantly, as did mean GAF score, all factors on the SF-36 and patient satisfaction with treatment. Scores on ESRS showed significant, sustained improvements throughout the study period. Direct initiation of RLAI was effective and well tolerated. RLAI provides an advancement in the treatment options available for a wide range of patients requiring long-term antipsychotic therapy.
Long-term remission in schizophrenia and related psychoses with long-acting risperidone: results obtained in an open-label study with an observation period of 18 months.
Llorca P-M,Sacchetti E,Lloyd K,Kissling W,Medori R
International journal of clinical pharmacology and therapeutics
OBJECTIVE:To monitor long-term symptomatic tolerability and remission in patients with stable but suboptimally treated psychoses after switching to risperidone long-acting injectable (RLAI). METHOD:This subgroup analysis of the Switch to Risperidone Microspheres (StoRMi) open-label trial followed up patients with psychoses who were converted to RLAI for a period of 18 months or until RLAI became commercially available in their country of residence. It included patients from seven European countries. Dosage adjustments were performed as clinically necessary. The efficacy endpoint was achieving and maintaining remission, defined as absent to mild core schizophrenia symptoms for > or = 6 months. A schizophrenia assessment was also completed and patients were monitored for the development of adverse events (AEs). Discontinuation rates were calculated based on Kaplan-Meier estimates where patients switching to commercial RLAI were used as censored observations. RESULTS:A total of 529 patients were followed for up to 18 months. At 18 months, the discontinuation rate was 55.7% based on Kaplan-Meier estimates. The median time to discontinuation was 15.7 months (95% CI (14.0; 17.5)). RLAI was generally well tolerated with most AEs mild-to-moderate in severity. 13% of patients discontinued treatment because of an AE. Body weight of patients increased by a mean A+/- SD of 1.0 A+/- 6.1 kg from treatment initiation to endpoint (p = 0.0001). Glucose-related AEs occurred in four patients (0.8%). Among those patients not meeting severity remission criteria at baseline, 44.8% were in remission at endpoint. Among those patients meeting severity criteria for remission at baseline, 84.2% were in remission at endpoint. A total of 93.7% of the patients who achieved or maintained remission at 6 months were in remission at endpoint. CONCLUSIONS:RLAI is safe during long-term treatment up to 18 months in adults requiring antipsychotics. Conversion to RLAI resulted in improved symptom control. Most patients achieved and maintained a sustained remission (> or = 6 months) after conversion to RLAI.
Direct transition to long-acting risperidone--analysis of long-term efficacy.
Kissling W,Heres S,Lloyd K,Sacchetti E,Bouhours P,Medori R,Llorca P M
Journal of psychopharmacology (Oxford, England)
This report presents data from the extension phase of a 6-month trial that evaluated the efficacy of risperidone long-acting injectable (RLAI) in stable psychotic patients requiring a treatment change. Patients continued to receive RLAI every 2 weeks for a maximum of 12 months from study entry. Symptoms were assessed using the PANSS after 1, 3, 6, 9 and 12 months of treatment (or treatment endpoint). Remission of severity criteria were defined as < or =3 points in all PANSS items suggested by the Remission in Schizophrenia Working Group.715 patients (63% male) entered the extension phase and 508 completed the 12-month study. The mean PANSS total score at Day 0 was 74.9+/-22.7. This was significantly reduced after 1 month (67.7 +/-22.3, p< or =0.001), with continued improvements over the 12 months of the study until treatment endpoint (59.7+/-21.9). Significant improvements from Day 0 to endpoint were also seen in the scores for all PANSS subscales and symptom factors. The proportion of patients who met the PANSS severity criteria for remission increased from 29% at Day 0 to 60% at endpoint, and the proportion of patients who met these criteria for < or = 6 months increased from 24% at Month 6 to 45% at endpoint. Treatment with RLAI for up to 12 months provided significant and sustained improvements in symptom control in patients with schizophrenia. These improvements may help patients to achieve and remain in remission.
Establishing remission and good clinical functioning in schizophrenia: predictors of best outcome with long-term risperidone long-acting injectable treatment.
Lambert M,De Marinis T,Pfeil J,Naber D,Schreiner A
European psychiatry : the journal of the Association of European Psychiatrists
OBJECTIVE:To measure symptomatic and functional remission in patients treated with risperidone long-acting injectable (RLAI). METHODS:Stable patients with psychotic disorders requiring medication change were switched to open-label RLAI in the switch to risperidone microspheres (StoRMi) trial. In this post-hoc analysis of the trial extension, follow-up was <or=18 months. Symptomatic remission was based on improvement in positive and negative syndrome scale (PANSS) scores and global remission (best outcome) was based on symptomatic remission, functional level, and mental-health quality of life. Predictive factors were evaluated. RESULTS:Among 529 patients from seven European countries, mean participation duration was 358.7+/-232.4 days, with 18 months completed by 39.9% of patients. Symptomatic remission lasting >or=6 months occurred at some point during treatment in 33% of patients; predictors included comorbid disease, country, baseline symptom severity, baseline functioning, type of antipsychotic before switching, and duration of untreated psychosis. Best outcome occurred in 21% of patients; predictors included baseline symptom severity, baseline functioning, country, schizophrenia type, and early positive treatment course. CONCLUSIONS:One in three patients with stable schizophrenia switching to RLAI experienced symptomatic remission, with combined symptomatic, functional, and quality-of-life remission in one in five patients. Symptomatic remission was predicted by better baseline symptom severity and country of origin, with a significantly greater likelihood of remission occurring among patients in Estonia/Slovenia compared with Portugal. Relapse was predicted by higher mode doses of RLAI, additional use of psychoactive medications, male gender, and country of origin, with relapse occurring most frequently in France and least frequently in Portugal. RLAI dose, additional use of psychoactive medications, and country of origin predicted best outcome, with best outcome occurring most frequently in Estonia/Slovenia and least frequently in Portugal.
[Long-acting injectable risperidone: naturalistic study in three hospitals in Aquitaine].
Raignoux C,Dusouchet T,Bret P,Queuille E,Biscay M-L,Caron J,Bret M C
INTRODUCTION:Injectable risperidone is the first long-acting second-generation antipsychotic. A middle-term naturalistic study has been conducted with the first treated patients of three psychiatric hospitals in Aquitaine. METHOD:Two evaluations of these patients were performed by psychiatrists: the first before the beginning of treatment and the second after six months. Data on efficacy and tolerance of the drug were obtained from in-patients who were unstable or non-compliant with their previous treatment. Two scales were used to highlight efficacy (positive and negative syndrome scale (PANSS) and clinical global impression (CGI)). All adverse events had to be notified in a general form and AIMS was used for extrapyramidal symptoms. Patient's quality of life was auto-evaluated by TEAQV. The pain on injection was assessed by the patients on a visual analogic scale. RESULT:Patients were treated between February 4th and December 4th 2004. Among the 71 treated patients, 27 (38%) discontinued treatment before the six months, due to: lost to follow-up (11.3%), consent withdrawn (9.9%), insufficient response (7%), adverse event (2.8%) or unknown reason (7%). The results of efficacy and tolerance concern 37 patients (52%) with a mean age of 32.8 (+/-7.8) years. Patient's PANSS score was 86.6 (+/-21.4) at the beginning of treatment. Mean decrease of this score was 13.2 after six months. Efficacy of the product is shown by 40.5% of the patients who decreased more than 20% of their initial PANSS score. CGI showed a global improvement "mild" to "great" with 46% of "strongly" to "very strongly" improved patients. Adverse reactions reported are known with risperidone: extrapyramidal symptoms (29.7%), weight gain (13.5%), dry-mouth syndrome (13.5%), hypotension (8.1%), sexual disorders (5.4%) and hyperprolactinemia (2.7%). Extrapyramidal symptoms were still the most common adverse events, as in the initial evaluation. Patients claimed their quality of life was unchanged after six months in comparison with the initial evaluation. They evaluated pain at injection site as moderate (2.6/10). DISCUSSION:The results of efficacy have been compared to the results published in the two studies that made it possible to obtain marketing autorisation of the drug in USA. The PANSS results for efficacy were not statically different from the results of the two reference studies (except for negative symptoms: there was no statistical difference observed between initial and final scores in our study, probably due to the small size of the sample). This study highlights several positive aspects for long-acting injectable risperidone (innovating pharmaceutical presentation: aqueous suspension which contains microspheres, moderate pain at injection site, efficacy in 40.5% of initially unstable patients, discharge and no rehospitalisation in most patients, decrease of the use of anticholinergic products) but also shows several negative aspects (frequency of injections--every two weeks--, high percentage of treatment discontinuation, same adverse event profile as oral risperidone, no improvement in quality of life). CONCLUSION:Despite the small size of the sample, this study presents a view of the use of the drug in realistic conditions and appears to show that long-acting injectable risperidone is probably the most appropriate treatment for stable, discharged patients.
Risperidone long-acting injection: in bipolar I disorder.
Deeks Emma D
A long-acting intramuscular formulation of the atypical antipsychotic agent risperidone is now indicated for the maintenance treatment of patients with bipolar I disorder. The formulation utilizes a novel drug delivery system of biodegradable microspheres and is bioequivalent to the oral formulation of the drug. Moreover, fluctuations in plasma drug concentrations at steady state were 1.7-fold lower with long-acting than with oral risperidone. Maintenance treatment with risperidone long-acting injection, as monotherapy in adults with stabilized bipolar I disorder or as an adjunct to standard therapy in adults with stabilized, frequently relapsing bipolar I disorder, was effective in delaying relapse to symptoms in two well designed trials with maintenance phases of 1 or 2 years' duration. The time to relapse to any mood episode (primary endpoint) was significantly longer with risperidone long-acting injection than with placebo in both studies. Risperidone long-acting injection also significantly reduced the risk of relapse relative to placebo in these trials. Maintenance treatment with risperidone long-acting injection was generally well tolerated in patients with bipolar disorder, both as monotherapy and adjunctive therapy, with most adverse reactions being of mild to moderate severity.
Long-term safety and efficacy of long-acting risperidone in elderly psychotic patients.
Kissling Werner,Glue Per,Medori Rossella,Simpson Steve
This subgroup analysis of the 6-month, open-label Switch to Risperidone Microspheres (StoRMi) trial evaluated long-term safety and efficacy of a direct conversion to risperidone long-acting injectable (RLAI) in 52 elderly patients (> or =65 years) with psychosis stabilized on oral or depot antipsychotic. Study outcomes included adverse events, movement disorder severity, psychiatric symptoms, functional ability, quality of life and patient satisfaction. Change in the Positive and Negative Syndrome Scale at endpoint was the primary efficacy measure. The most common dosage of RLAI used at endpoint was 25 mg every 14 days (60%). The trial was completed by 81% of patients, with six patients discontinuing treatment due to an adverse event. Tolerability was good and most side effects were mild to moderate. Serious adverse events occurred in 11 patients. Two of these (suicidal attempt, n = 1; exacerbation of disease, n = 1) were considered possibly related to RLAI. Conversion to RLAI resulted in significant improvements in movement disorder severity, psychiatric symptoms, functional status and patient satisfaction. Mean PANSS total decreased by 15.8 at endpoint, with 23 patients (46.9%) experiencing a > or =20% improvement. This post-hoc analysis supports that RLAI is well tolerated and safe in elderly patients with psychotic illnesses switched from stable antipsychotic regimens, and suggests possible efficacy, although inferences are limited.
Long-acting risperidone improves negative symptoms in stable psychotic patients.
Curtis V A,Katsafouros K,Möller H-J,Medori R,Sacchetti E
Journal of psychopharmacology (Oxford, England)
The aim of this paper was to evaluate the efficacy of risperidone long-acting injectable (RLAI) for reducing negative symptoms of schizophrenia in patients with predominantly negative symptoms at baseline. A subanalysis was performed on data from the 6-month, open-label Switch to Risperidone Microspheres trial. Patients with Positive and Negative Syndrome Scale (PANSS) negative subscale score > or = 21, which was higher than their PANSS positive subscale score, were included in this subanalysis. Improvement in negative symptoms was measured by assessing change in the PANSS negative subscale and a negative factor score. Additional outcome variables included measures in general functioning, quality of life and patient satisfaction. A total of 842 patients were eligible for inclusion in this subanalysis. Six months of treatment was completed by 631 (74.9%) patients. Forty-three (5.1%) patients discontinued treatment due to an adverse event. Negative symptoms were significantly reduced by 6.1 +/- 6.3 points for the PANSS negative score and 6.1 +/- 6.4 points for the negative factor score (P < 0.0001 for both). Significant improvements were also noted for total PANSS and other PANSS subscale scores, general functioning, quality of life and patient satisfaction (P < 0.0001). The most common treatment-emergent adverse events (>5%) were: anxiety (6.8% of patients), exacerbation of disease (6.2%) and insomnia (5.7%). Overall, RLAI was well tolerated and associated with significant reductions in movement disorder severity. The treatment resulted in a significant improvement in negative symptom severity and was well tolerated in patients with predominantly negative symptoms, who switched from a stable antipsychotic regimen
Prospective, open study of long-acting injected risperidone versus oral antipsychotics in 88 chronically psychotic patients.
Girardi P,Serafini G,Pompili M,Innamorati M,Tatarelli R,Baldessarini R J
INTRODUCTION:A long-acting, injected, carbohydrate-microsphere preparation of risperidone (RLAI; Risperdal Consta ((R))) is reported to be safe and effective in chronic psychotic illnesses but, as its long-term and comparative efficacy remain unclear, this study compared clinical status during oral antipsychotic treatment versus conversion to RLAI. METHODS:Psychotic patients (n=88; initial BPRS=93+/-5) were treated for 6 months with clinically chosen oral medication and then converted to biweekly RLAI for the first 6 months (6-6 months matched mirror comparison) and then for another 18 months. Clinical status in the two treatment periods and in the 18 months of follow-up was compared with measures including BPRS improvement (primary outcome), CGI variants and SF-36 ratings. RESULTS:RLAI (at a mean dose of 47 mg/2 weeks at six and up to 23.1+/-3.3 months) was associated with major improvements in all outcome measures (p<0.001). Initial BPRS scores fell by an average of 50% within six months; hospitalizations declined from 19.8% to 0%, and rates of adverse events were reduced by 2.5- to 7.4-fold. Such benefits were sustained during 18 months of follow-up with RLAI-treatment. CONCLUSIONS:The findings are limited by the lack of a parallel control treatment, such as with oral risperidone or another antipsychotic, lack of blinded assessments, and a moderate number of subjects. Nevertheless, the findings add to indications that RLAI can be an effective and well-tolerated treatment-option for chronically psychotic patients.
Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study.
Weiden Peter J,Schooler Nina R,Weedon Jeremy C,Elmouchtari Abdel,Sunakawa-McMillan Ayako
The Journal of clinical psychiatry
BACKGROUND:Because long-acting injectable (LAI) antipsychotics are largely reserved for persistently ill patients, little is known about the use of LAIs early in the course of illness for first-episode outpatients. METHOD:A prospective, open-label, randomized controlled trial was conducted in which outpatients with first-episode DSM-IV schizophreniform disorder, schizophrenia, or schizoaffective disorder were enrolled from December 2004 to March 2007. Participants were randomly assigned at a 2:1 ratio to a recommendation of changing to LAI risperidone microspheres (RLAI) (n = 26) or continuing oral antipsychotic treatment (n = 11) for up to 104 weeks. Primary outcomes were time until initial nonadherence (medication gap of ≥ 14 days) and medication attitudes as assessed with the Rating of Medication Influences scale. Patients randomly assigned to an RLAI recommendation could decline the recommendation, so analysis defined treatment groups by intent-to-treat and as-actually-treated. RESULTS:Eighty-one percent of patients (30/37) stopped medication within 104 weeks. There was a trend toward an initial adherence benefit favoring RLAI acceptors at 12 weeks (P = .058), but no significant difference between RLAI and oral antipsychotic treatment in time to initial nonadherence during the overall study (P = .188). Medication attitudes did not differ between groups. CONCLUSIONS:Acceptance of RLAI was associated with an initial adherence benefit that was not sustained over time. Early introduction of LAI therapy did not adversely affect adherence attitudes. The small size of the study and low power limit interpretation, but the few patients who remained adherent into a second year were all receiving RLAI. Nonadherence was almost universal in our first-episode cohort, but nonadherence was more easily detected among first-episode patients treated with LAI therapy than it was with oral antipsychotics. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00220714.
Use of therapeutic drug monitoring of risperidone microspheres long-acting injection in hemodialysis: A case report.
Tourtellotte Rebecca,Schmidt Robert
The mental health clinician
Limited evidence exists for the use of psychiatric medications in patients with end-stage renal disease on hemodialysis. Many psychotropic medications are not well-studied in this population, and optimal dosing of these medications is not well-established. Therapeutic drug monitoring is a useful tool in assessing the safety and efficacy of psychotropic medications; however, the use is unclear with long-acting injectable antipsychotics. We present a case of a 73-year-old male initiated on hemodialysis while on risperidone microspheres long-acting injection (RMLAI). Risperidone and 9-hydroxyrisperidone plasma concentrations obtained from this patient were relatively similar before and after initiation of hemodialysis, therefore it appears hemodialysis does not significantly influence clearance of RMLAI. Plasma concentrations in this patient were higher than those reported in the literature for equivalent doses, which may indicate accumulation of the medication secondary to renal impairment.