Comparison of Efficacy and Safety between Long-Acting Injectable Antipsychotic Monotherapy and Combination of Long-Acting Injectable and Oral Antipsychotics in Patients with Schizophrenia

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

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

Background and importanceTreatment with long acting injectable (LAI) antipsychotics has been shown to improve treatment adherence compared with oral antipsychotics, but it is still controversial if adherence is modified with...

Disease relapse, all-cause mortality, and adverse events associated with long-acting injectable antipsychotics versus oral antipsychotics in older people with schizophrenia in Hong Kong: a population-based within-subject analysis.

Introduction:Despite the theory that long-acting injectable (LAI) antipsychotics should be more likely to improve adherence, reduce gaps in therapy, and prevent relapse compared with oral antipsychotics, there is little published evidence on this issue, specifically in patients with early psychosis.Methods:Patients with a new diagnosis for a psychotic disorder between July 1, 2013, and August 31, 2014, were retrospectively evaluated during a 12-month duration. The primary outcomes were adherence and persistence. Adherence was determined by proportion of days with medication, and persistence was defined as zero gaps in medication therapy. The secondary outcome was the number of times a psychiatric acute care service was used. Patients were divided into 3 groups based on their antipsychotic prescription history: oral only, LAI only, or both formulations at separate times throughout the study period.Results:Forty-seven patients met inclusion criteria. The average proportions of days with medication were 32%, 76%, and 75% for the oral, LAI, and both formulations groups, respectively (P < .001). For medication persistence, there were 32 patients (91%), 3 patients (75%), and 5 patients (63%) with at least 1 gap in therapy for the oral, LAI, and both formulations groups, respectively (P = .098). For acute care services, there was a median number of zero acute care visits for each of the 3 groups (P = .179). A post hoc subgroup analysis found medication adherence to be statistically different between the oral and LAI groups.Discussion:Long-acting injectable antipsychotics were associated with better adherence compared with oral antipsychotics in patients with early psychosis.

Schizophrenia is a chronic, debilitating mental illness that incurs a large economic burden. Decreasing hospital readmissions is a priority in health care to improve patient quality of life and decrease health care costs. Determining ways to prevent readmissions such as improving access to long-acting injectable (LAI) antipsychotics is important to assess. A single-center retrospective review was conducted comparing readmission rates of patients diagnosed with schizophrenia or schizoaffective disorder discharged on LAI or oral antipsychotics between August 1, 2019, and June 30, 2022. The primary outcome was the 30-day psychiatric readmission rate. Secondary outcomes included chlorpromazine equivalent doses and use of anticholinergic medications. The 30-day readmission rate was 1.9% for the LAI antipsychotic group and 8.3% for the oral antipsychotic group ( P = 0.03; 95% confidence interval, 1.05-20.02). The average chlorpromazine equivalent antipsychotic dose of patients discharged on LAI versus oral antipsychotic medications was 477.3 and 278.6 mg/d, respectively ( P < 0.001). In addition, the prevalence of medications used to treat extrapyramidal symptom was 22.3% (n = 23) for the LAI antipsychotic group and 30.8% (n = 74) for the oral antipsychotic group ( P = 0.12). Sixty-four percent of LAI antipsychotics utilized were obtained from pharmaceutical company hospital inpatient free trial programs. Long-acting injectable antipsychotics showed a statistically significant reduction in 30-day rehospitalizations as compared with oral antipsychotics and hospital inpatient free trial programs aided in LAI antipsychotic acquisition.

PurposeTo describe (1) the clinical profiles and the patterns of use of long-acting injectable (LAI) antipsychotics in patients with schizophrenia at risk of nonadherence with oral antipsychotics, and in those who started treatment with LAI antipsychotics, (2) health care resource utilization and associated costs.Patients and methodsA total of 597 outpatients with schizophrenia at risk of nonadherence, according to the psychiatrist’s clinical judgment, were recruited at 59 centers in a noninterventional prospective observational study of 1-year follow-up when their treatment was modified. In a post hoc analysis, the profiles of patients starting LAI or continuing with oral antipsychotics were described, and descriptive analyses of treatments, health resource utilization, and direct costs were performed in those who started an LAI antipsychotic.ResultsTherapy modifications involved the antipsychotic medications in 84.8% of patients, mostly because of insufficient efficacy of prior regimen. Ninety-two (15.4%) patients started an LAI antipsychotic at recruitment. Of these, only 13 (14.1%) were prescribed with first-generation antipsychotics. During 1 year, 16.3% of patients who started and 14.9% of patients who did not start an LAI antipsychotic at recruitment relapsed, contrasting with the 20.9% who had been hospitalized only within the prior 6 months. After 1 year, 74.3% of patients who started an LAI antipsychotic continued concomitant treatment with oral antipsychotics. The mean (median) total direct health care cost per patient per month during the study year among the patients starting any LAI antipsychotic at baseline was €1,407 (€897.7). Medication costs (including oral and LAI antipsychotics and concomitant medication) represented almost 44%, whereas nonmedication costs accounted for more than 55% of the mean total direct health care costs.ConclusionLAI antipsychotics were infrequently prescribed in spite of a psychiatrist-perceived risk of nonadherence to oral antipsychotics. Mean medication costs were lower than nonmedication costs.

Patients with schizophrenia receiving antipsychotic treatment present lower mortality rates than those who do not. However, the non-adherence rate is high, which can be partially addressed using long-acting injectable (LAI) antipsychotics. The impact of LAI treatments on all-cause mortality compared to oral antipsychotics remains unclear. To fill that gap, a random effects meta-analysis was conducted to analyze the odds ratio (OR) of all-cause, suicidal, and non-suicidal mortality among patients taking LAI antipsychotics compared to oral antipsychotics (PROSPERO:CRD42023391352). Individual and pooled LAI antipsychotics were analyzed against pooled oral antipsychotics. Sensitivity analyses were performed for study design, setting, and industry sponsorship. Meta-regressions were conducted for gender, age, antipsychotic dose, and race. Seventeen articles, total sample 12,042 patients (N = 5795 oral, N = 6247 LAI) were included. Lower risk of all-cause mortality for patients receiving LAI antipsychotics vs receiving oral antipsychotics was found (OR = 0.79; 95%CI = 0.66–0.95). Statistical significance was maintained when only studies comparing the same LAI and oral antipsychotic were included (OR = 0.79; 95%CI = 0.66–0.95; p = <0.01), as well as for non-suicidal mortality (OR = 0.77: 95%CI = 0.63–0.94; p = 0.01), but not for suicidal mortality (OR = 0.86; 95%CI = 0.59–1.26; p = 0.44). Mortality reduction was more pronounced for LAI antipsychotics in first-episode psychosis (FEP) (OR = 0.79; 95%CI = 0.66–0.96) compared to chronic psychosis. No individual LAI reported statistically significant differences against all pooled oral antipsychotics. LAI antipsychotics are associated with a lower risk of all-cause and non-suicidal mortality in individuals with schizophrenia compared to oral antipsychotics. Better adherence to the medication and health services may explain this difference. Whenever possible, the use of LAIs should be considered from the FEP.

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

Long-acting injectable (LAI) antipsychotics (LAI-APs) have several advantages over oral medications, but deaths reported in Japan during the early post-marketing phase vigilance period have raised safety concerns. We conducted a series of meta-analyses to assess whether LAI-APs affect the mortality of patients with schizophrenia. Three categorical meta-analyses of randomized controlled trials (RCTs) were performed to compare all-cause death (primary outcome) and death due to suicide: individual and pooled LAI-APs vs placebo, individual and pooled LAI-APs vs oral antipsychotics (OAPs), and head-to-head comparisons of LAI-APs. The risk ratios (RRs) and 95% CIs were calculated. We identified 52 RCTs (53 comparisons; total participants = 17 416, LAI-APs = 11 360, OAP = 3910, and placebo = 2146; mean study duration [wk]: LAI-APs vs placebo = 28.9, LAI-APs vs OAPs = 64.5). Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone, and risperidone) differed from the placebo regarding the incidences of all-cause death (pooled LAI-APs: RR = 0.64, P = .37) and death due to suicide (pooled LAI-APs: RR = 0.98, P = .98). However, in a subgroup meta-analysis of only short-duration RCTs (≤13wk), pooled LAI-APs exhibited a trend toward lower incidence of all-cause death than placebo (RR = 0.29, P = .08). Pooled LAI-APs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol) did not differ from pooled OAPs regarding all-cause death (pooled LAI-APs: RR = 0.71, P = .30) and death due to suicide (pooled LAI-APs: RR = 0.94, P = .91). Individual LAI-APs and OAPs were associated with similar risks of death. Data for head-to-head comparisons of individual LAI-APs were insufficient. In conclusion, there was no significant difference between LAI-APs and placebo or OAPs regarding all-cause death and death due to suicide.

Schizophrenic patient’s preference for long-acting injectable antipsychotics in Saudi Arabia

BackgroundLong-acting injectable (LAI) antipsychotics, compared with oral antipsychotics (OA), have been found to significantly improve patient outcomes, including reduced hospitalizations and emergency room (ER) admissions and increased medication adherence among adult patients with schizophrenia. In turn, the clinical benefits achieved may translate into lower economic burden. Real-world evidence of the comparative effectiveness of LAI is needed to understand the potential benefits of LAI outside of the context of clinical trials. This study aimed to provide a comprehensive synthesis of recent published real-world studies comparing healthcare utilization, costs, and adherence between patients with schizophrenia treated with LAI versus OA in the United States.MethodsIn this systematic literature review, MEDLINE® was searched for peer-reviewed, real-world studies (i.e., retrospective or pragmatic designs) published in English between January 1, 2010 and February 10, 2020. Comparative studies reporting hospitalizations, ER admissions, healthcare costs, or medication adherence (measured by proportion of days covered [PDC]) in adults with schizophrenia treated with LAI versus OA (or pre- vs post-LAI initiation) in the United States were retained. Random effects meta-analyses were conducted among eligible studies to evaluate the association of LAI versus OA use on hospitalizations, ER admissions, healthcare costs, and treatment adherence. A sensitivity analysis among the subset of studies that compared OA with paliperidone palmitate once monthly (PP1M), specifically, was conducted.ResultsA total of 1083 articles were identified by the electronic literature search, and two publications were manually added subsequently. Among the 57 publications meeting the inclusion criteria, 25 provided sufficient information for inclusion in the meta-analyses. Compared with patients treated with OA, patients initiated on LAI had lower odds of hospitalization (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.54–0.71, n = 7), fewer hospitalizations (incidence rate ratio [IRR] [95% CI] 0.75 [0.65–0.88], n = 9), and fewer ER admissions (IRR [95% CI] 0.86 [0.77–0.97], n = 6). The initiation of LAI was associated with higher per-patient-per-year (PPPY) pharmacy costs (mean difference [MD] [95% CI] $5603 [3799–7407], n = 6), which was offset by lower PPPY medical costs (MD [95% CI] − $5404 [− 7745 to − 3064], n = 6), resulting in no significant net difference in PPPY total all-cause healthcare costs between patients treated with LAI and those treated with OA (MD [95% CI] $327 [− 1565 to 2219], n = 7). Patients initiated on LAI also had higher odds of being adherent to their medication (PDC ≥ 80%; OR [95% CI] 1.89 [1.52–2.35], n = 9). A sensitivity analysis on a subset of publications evaluating PP1M found results similar to those of the main analysis conducted at the LAI class level.ConclusionsBased on multiple studies with varying sub-types of patient populations with schizophrenia in the United States published in the last decade, this meta-analysis demonstrated that LAI antipsychotics were associated with improved medication adherence and significant clinical benefit such as reduced hospitalizations and ER admissions compared with OA. The lower medical costs offset the higher pharmacy costs, resulting in a non-significant difference in total healthcare costs. Taken together, these findings provide strong evidence on the clinical and economic benefits of LAI compared with OA for the treatment of schizophrenia in the real world.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00815-y.

BackgroundSchizophrenia often requires long-term treatment with antipsychotics. Paliperidone palmitate long-acting injection (PPLAI) is one of the advantageous options to maintain adherence, prevent relapse and hospitalization (Kishimoto et al., 2021; Tiihonen et al., 2017). In Japan, paliperidone palmitate 1-monthly (PP1M) and paliperidone palmitate 3-monthly (PP3M) have been approved, and the approved patient population for PP3M in Japan is limited to patients with schizophrenia who have been stabilized with PP1M monotherapy. Antipsychotic polypharmacy consisting of LAI and oral antipsychotics (OAPs) are widely used in the clinical practice in many countries (Doshi et al., 2015; Aggarwal et al., 2012; Dimitropoulos et al., 2017; Cordiner et al., 2016; Joo et al., 2019), including Japan (Onitsuka et al., 2023). Hence, LAI monotherapy may be a more appropriate option in the long term. However, to date, factors associated with continuation for LAI monotherapy have not been examined. Therefore, we conducted a post-hoc analysis of a post-marketing surveillance (PMS) to explore factors associated with subsequent treatment continuation in patients who introduced PP1M monotherapy.Aims & ObjectivesThe purpose of the post-hoc analysis is to identify factors associated with subsequent treatment continuation in schizophrenia patients in whom PP1M was introduced as a monotherapy.MethodThis study is a post-hoc analysis of the PMS in PP1M in Japan. The case enrollment period was from January 2014 to July 2015, and patients with schizophrenia who received PP1M according to the dosage and administration in the package insert were enrolled. The primary analysis population will be 698 of the 1306 patients enrolled in the PMS who were being treated with PP1M monotherapy treatment at the start of PP1M. Main endpoint will include time to drop out of monotherapy (all causes of dropping PP1M monotherapy). Factors associated with continuation of PP1M monotherapy will be assessed by using cox regression model. In this presentation, we will report on factors associated with subsequent treatment continuation in schizophrenia patients where PP1M was introduced as monotherapy.ReferencesKishimoto, T., Hagi, K., Kurokawa, S., Kane, J. M., &Correll, C. U. (2021). 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. The lancet. Psychiatry, 8(5), 387–404. https://doi.org/10.1016/S2215-0366(21)00039-0Tiihonen, J., Mittendorfer-Rutz, E., Majak, M., Mehtä lä, J., Hoti, F., Jedenius, E., Enkusson, D., Leval, A., Sermon, J., Tanskanen, A., &Taipale, H. (2017). Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29823 Patients With Schizophrenia. JAMA psychiatry, 74(7), 686–693. https://doi.org/10.1001/jamapsychiatry.2017.1322Doshi, J. A., Pettit, A. R., Stoddard, J. J., Zummo, J., &Marcus, S. C. (2015). Concurrent Oral Antipsychotic Drug Use Among Schizophrenia Patients Initiated on Long-Acting Injectable Antipsychotics Post-Hospital Discharge. Journal of clinical psychopharmacology, 35(4), 442–446. https://doi.org/10.1097/JCP.0000000000000353Aggarwal, N. K., Sernyak, M. J., &Rosenheck, R. A. (2012). Prevalence of concomitant oral antipsychotic drug use among patients treated with long-acting, intramuscular, antipsychotic medications. Journal of clinical psychopharmacology, 32(3), 323–328. https://doi.org/10.1097/JCP.0b013e31825244f6Dimitropoulos, E., Drogemuller, L., &Wong, K. (2017). Evaluation of Concurrent Oral and Long-Acting Injectable Antipsychotic Prescribing at the Minneapolis Veterans Affairs Health Care System. Journal of clinical psychopharmacology, 37(5), 605–608. https://doi.org/10.1097/JCP.0000000000000755Cordiner, M., Shajahan, P., McAvoy, S., Bashir, M., &Taylor, M. (2016). Effectiveness of long-acting antipsychotics in clinical practice: 2. Effects of antipsychotic polypharmacy on risperidone long-acting injection and zuclopenthixol decanoate. Therapeutic advances in psychopharmacology, 6(2), 66–76. https://doi.org/10.1177/2045125315623584Joo, S. W., Shon, S. H., Choi, G., Koh, M., Cho, S. W., &Lee, J. (2019). Continuation of schizophrenia treatment with three long-acting injectable antipsychotics in South Korea: A nationwide population- based study. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(9), 1051–1060. https://doi.org/10.1016/j.euroneuro.2019.07.138Onitsuka, T., Okada, T., Hasegawa, N., Tsuboi, T., Iga, J. I., Yasui-Furukori, N., Yamada, N., Hori, H., Muraoka, H., Ohi, K., Ogasawara, K., Shinichiro, O., Takeshima, M., Ichihashi, K., Fukumoto, K., Iida, H., Yamada, H., Furihata, R., Makinodan, M., Takaesu, Y., … Hashimoto, R. (2023). Combination Psychotropic Use for Schizophrenia With Long-Acting Injectable Antipsychotics and Oral Antipsychotics: A Nationwide Real-World Study in Japan. Journal of clinical psychopharmacology, 10.1097/JCP.0000000000001704. Advance online publication. https://doi.org/10.1097/JCP.0000000000001704

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

Compared with oral antipsychotics (OAPs), long-acting injectable antipsychotics (LAIs) should improve medication adherence and reduce relapses in schizophrenia. However, meta-analyses of randomized trials and mirror-image studies yielded inconsistent results. Nonrandomized cohort studies with parallel comparisons of LAIs and OAPs offer a third design to examine this issue. We meta-analyzed cohort studies with ≥24 weeks duration and hospitalization data. Primary outcome was hospitalization rate, ie, number of hospitalizations per person-year. Secondary outcomes included hospitalization risk, ie, proportion of patients experiencing ≥1 hospitalizations, all-cause discontinuation, and total hospitalization days. Patient severity and/or chronicity at baseline was also meta-analyzed and explored as a potential effect size moderator. Altogether, 42 studies (n = 101 624; follow-up = 18.6 ± 10.0 mo) were meta-analyzed. LAIs were superior to OAPs regarding hospitalization rate (studies = 15, person-years = 68 009, rate ratio = 0.85, 95% CI = 0.78-0.93, P < .001) and all-cause discontinuations (studies = 10, n = 37 293, risk ratio = 0.78, 95% CI = 0.67-0.91, P = .001), but not regarding hospitalization risk (studies = 33, n = 51 733, risk ratio = 0.92, 95% CI = 0.84-1.00, P = .06), and hospitalization days (studies = 11, n = 21 328, Hedges' g = -0.05, 95% CI = -0.16 to 0.06, P = .39). Illness severity/chronicity was significantly greater in patients prescribed LAIs vs OAPs when all available information was pooled together (studies = 23, n = 61 806, Hedges' g = 0.15, 95% CI = 0.03-0.26, P = .01), but not when examined separately. In summary, this meta-analysis of cohort studies, which included patients that are broadly representative of clinical practice, indicates that LAIs are superior to OAPs. The lack of significant superiority of LAIs for hospitalization risk and hospital days needs to be interpreted in the context of naturalistic treatment selection with subsequently greater illness severity/chronicity in LAI-treated patients.