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Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials.

ABSTRACT: BACKGROUND:While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs). METHODS:Systematic review/meta-analysis of RCTs that lasted ? 6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation, discontinuation due to adverse events, drug inefficacy (ie, relapse + discontinuation due to inefficacy), hospitalization, and nonadherence. RESULTS:Across 21 RCTs (n = 5176), LAIs were similar to OAPs for relapse prevention at the longest time point (studies = 21, n = 4950, relative risk [RR] = 0.93, 95% confidence interval [CI]: 0.80-1.08, P = .35). The finding was confirmed restricting the analysis to outpatient studies lasting ? 1 year (studies = 12, RR = 0.93, 95% CI:0.71-1.07, P = .31). However, studies using first-generation antipsychotic (FGA)-LAIs (studies = 10, RR = 0.82, 95% CI:0.69-0.97, P = .02) and those published ? 1991 (consisting exclusively of all 8 fluphenazine-LAI studies; RR = 0.79, 95% CI: 0.65-0.96, P = 0.02) were superior to OAPs regarding the primary outcome. Pooled LAIs also did not separate from OAPs regarding any secondary outcomes. Again, studies using FGA-LAIs and those published ? 1991 were associated with LAI superiority over OAPs, eg, hospitalization and drug inefficacy. CONCLUSIONS:In RCTs, which are less representative of real-world patients than naturalistic studies, pooled LAIs did not reduce relapse compared with OAPs in schizophrenia patients. The exceptions were FGA-LAIs, mostly consisting of fluphenazine-LAI studies, which were all conducted through 1991. Because this finding is vulnerable to a cohort bias, studies comparing FGA-LAI vs second-generation antipsychotics-LAI and LAI vs OAP RCTs in real-world patients are needed.

SUBMITTER: Kishimoto T

PROVIDER: S-EPMC3885289 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials.

Kishimoto Taishiro T Robenzadeh Alfred A Leucht Claudia C Leucht Stefan S Watanabe Koichiro K Mimura Masaru M Borenstein Michael M Kane John M JM Correll Christoph U CU

Schizophrenia bulletin 20121217 1

<h4>Background</h4>While long-acting injectable antipsychotics (LAIs) are hoped to reduce high relapse rates in schizophrenia, recent randomized controlled trials (RCTs) challenged the benefits of LAIs over oral antipsychotics (OAPs).<h4>Methods</h4>Systematic review/meta-analysis of RCTs that lasted ≥ 6 months comparing LAIs and OAPs. Primary outcome was study-defined relapse at the longest time point; secondary outcomes included relapse at 3, 6, 12, 18, and 24 months, all-cause discontinuation ...[more]

PMID: 23256986

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Project description:ImportanceEvidence for improved clinical outcomes with long-acting injectable antipsychotics (LAIAs) vs oral antipsychotics (OAs) is limited in Asian populations and special patient groups, including older people (>65 years), people with substance use, and early initiators of LAIAs.ObjectiveTo compare the risk of disease relapse, health care use, and adverse events associated with the use of LAIAs vs OAs among people in Hong Kong with schizophrenia.Design, setting, and participantsIn this self-controlled case series study, individuals with a diagnosis of schizophrenia who were prescribed LAIAs and OAs between January 1, 2004, and December 31, 2019, were identified from the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority. Data analysis was conducted from May to August in 2021.ExposuresUse of LAIAs vs OAs.Main outcomes and measuresRisk of disease relapse (hospitalizations for psychiatric disorders, hospitalizations for schizophrenia, and suicide attempts), health care use (all-cause emergency department visits and hospitalizations), and adverse events (hospitalizations for somatic disorders, hospitalizations for cardiovascular diseases, and extrapyramidal symptoms) between the period in which patients were treated with LAIAs and the period in which patients were treated with OAs were compared using Poisson regression.ResultsOf the 70 396 individuals with schizophrenia (37 200 women [52.8%]; mean [SD] age, 44.2 [15.8] years), 23 719 (33.7%) were prescribed both LAIAs and OAs. Compared with OAs, LAIAs were associated with a lower risk of hospitalizations for any cause (n = 20 973; incidence rate ratio [IRR], 0.63 [95% CI, 0.61-0.65]), hospitalizations for psychiatric disorders (n = 19 283; IRR, 0.52 [95% CI, 0.50-0.53]), hospitalizations for schizophrenia (n = 18 385; IRR, 0.53 [95% CI, 0.51-0.55]), and incident suicide attempts (n = 1453; IRR, 0.56 [95% CI, 0.44-0.71]). During full treatment with LAIAs, there was a reduction in hospitalizations for somatic disorders (n = 15 396; IRR, 0.88 [95% CI, 0.85-0.91]), hospitalizations for cardiovascular diseases (n = 3710; IRR, 0.88 [95% CI, 0.81-0.96]), and extrapyramidal symptoms (n = 22 182; IRR, 0.86 [95% CI, 0.82-0.91]) compared with full treatment with OAs. No significant difference was found for emergency department visits. Similar associations were observed during the subsequent treatment periods (beyond 90 days) and among older people and those with substance use, except for an increased risk of extrapyramidal symptoms among older people when initiating LAIAs (first 90 days). Compared with late initiators, early LAIA initiators had a greater reduction in these outcome events.Conclusions and relevanceThis self-controlled case series study of people in Hong Kong with schizophrenia suggests that LAIAs were associated with a lower risk of disease relapse and hospitalization than OAs, without an increased risk of adverse events. Clinicians should more broadly consider the long-term use of LAIAs for Chinese people with schizophrenia, especially early in the course of illness.

Project description:BackgroundThis meta-analysis of randomized controlled trials aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder.MethodsTwo categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications.ResultsWe identified 7 randomized controlled trials (n=1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials)=449]; oral medications [mood stabilizers, antidepressants, antipsychotic, or any combination of these agents=283]; and placebo=284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate (risk ratio=0.63, P<.0001), relapse of manic symptoms (risk ratio=0.42, P<.00001), and all-cause discontinuation (risk ratio=0.75, P=.007). Risperidone-long-acting injectable was associated with higher incidence of prolactin-related adverse events (risk ratio=4.82, P=.001) and weight gain (risk ratio=3.80, P<.0001) than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I2=74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications (I2=0%, RR=0.58, P=.0004). However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, long-acting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with higher incidence of prolactin-related adverse events than oral medications (RR=2.66, P=.03).ConclusionsLong-acting injectable antipsychotics appear beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.

Project description:IntroductionLong-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs.MethodsWe used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA]).ResultsOne hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98-2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59-1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66-1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52-1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58-3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56-9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19-4.96); higher antipsychotic dose (>2DDDs-OR: 3.15, 95% CI: 1.61-6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57-3.24), lithium (OR: 2.16, 95% CI: 1.30-3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44-3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22-2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77-839) days after rechallenge with antipsychotics.ConclusionNMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality.

Project description: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.

Project description:ImportanceSchizophrenia is generally considered to be among the most severe psychiatric disorders because of the excessive mortality associated with it. Research to find means to reduce this excessive mortality is warranted.ObjectiveTo investigate associations of long-acting injectable antipsychotics (LAIs) with all-cause, natural-cause, and suicide mortality risks as well as the impacts of early use of LAIs in patients with newly diagnosed schizophrenia.Design, setting, and participantsThis cohort study used data from the Taiwan National Health Insurance Research Database to construct a population-based cohort of patients with schizophrenia who received oral antipsychotics (OAPs) from January 1, 2002, to December 31, 2017. Within this cohort, the LAI group was defined as patients who switched to LAIs and were prescribed LAIs at least 4 times within 1 year. The LAI group was propensity matched 1:1 to patients who continued receiving OAPs of the same compounds. All patients were followed up until switching the antipsychotic administration route, death, or the end of the study (December 31, 2018), whichever occurred first. Data analysis was performed from January 2002 to December 2018.Main outcomes and measuresAll-cause mortality, natural-cause mortality, suicide mortality, and suicide attempts.ResultsIn total, 2614 patients who switched to LAIs (median [interquartile range] {IQR} age, 30 [23-39] years) and 2614 who received OAPs (median [IQR] age, 30 [23-39] years) were included (1333 male patients [51.0%] in each group). During the 16-year follow-up period (median [IQR] follow-up of 14 [10-17] years), patients who switched to LAIs had lower risks of all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.54-0.81), natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93) compared with patients who received the corresponding OAPs. A 47% lower suicide mortality risk (aHR, 0.53; 95% CI, 0.30-0.92) was observed in patients who switched to LAIs within the first 2 years of OAP initiation.Conclusions and relevanceThese findings suggest that LAI use in patients with newly diagnosed schizophrenia is associated with decreased all-cause mortality and suicide risk. Furthermore, early treatment with LAIs within the first 2 years of OAP initiation was associated with a decrease in suicide mortality risk. Thus, LAI use in the early stage of treatment should be actively considered for patients with newly diagnosed schizophrenia.

Project description:Chronic management of schizophrenia and schizoaffective disorders is frequently complicated by symptomatic relapse. An open-label, randomized, active-controlled, 2-year trial evaluated 710 patients with schizophrenia or related disorders who were switched from stable treatment with oral risperidone, olanzapine, or conventional neuroleptics to risperidone long-acting injectable (RLAI) or oral quetiapine. Primary effectiveness evaluation was time-to-relapse. Safety evaluations included adverse events (AEs) reported for the duration of the study, Extrapyramidal Symptom Rating Scale (ESRS), clinical laboratory tests, and vital signs. A total of 666 patients (n=329 RLAI, n=337 quetiapine) were evaluable for effectiveness measures. Baseline demographics were similar between treatment groups. Kaplan-Meier estimate of time-to-relapse was significantly longer with RLAI (p<0.0001). Relapse occurred in 16.5% of patients with RLAI and 31.3% with quetiapine. RLAI and quetiapine were both safe and well tolerated. Weight gain affected 7% of patients with RLAI and 6% with quetiapine, with mean end point increases of 1.25±6.61 and 0±6.55 kg, respectively. There were no significant between-group differences in weight gain. ESRS total scores decreased similarly after randomization to either RLAI or quetiapine. Extrapyramidal AEs occurred in 10% of patients with RLAI and 6% with quetiapine. Treatment-emergent potentially prolactin-related AEs were reported in 15 (5%) patients with RLAI and 5 (2%) patients with quetiapine; hyperprolactinemia was reported in 43 (13.1%) patients with RLAI and 5 (1.5%) patients with quetiapine. Somnolence occurred in 2% of patients with RLAI and 11% with quetiapine. To our knowledge, this is the first report of a randomized clinical trial directly comparing relapse prevention with a second-generation long-acting injectable antipsychotic and oral therapy. Time-to-relapse in stable patients with schizophrenia or schizoaffective disorder was significantly longer in patients randomized to RLAI compared with those randomized to oral quetiapine. Both antipsychotics were generally well tolerated.

Project description:BackgroundThis post hoc subgroup analysis of a randomized, double-blind trial evaluated the response to treatment with two long-acting injectable atypical antipsychotics, ie, paliperidone palmitate and risperidone long-acting injectable (RLAI), in subjects with schizophrenia experiencing clinically significant symptoms despite recent treatment with oral risperidone only or other oral antipsychotics.MethodsAdult subjects were eligible for the 13-week, double-blind, double-dummy trial (NCT00589914) if they had an established diagnosis of schizophrenia for at least one year and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 inclusive at screening. Subjects received either paliperidone palmitate (234 mg, day 1; 156 mg, day 8; then once-monthly flexible dosing) or RLAI (25-50 mg biweekly, with oral risperidone supplementation on days 1-28), plus matched placebo injections/tablets.ResultsThis post hoc analysis reports data on 747 subjects who, within 2 weeks of starting double-blind study medication, had reportedly received oral risperidone only (paliperidone palmitate group, n = 126; RLAI group, n = 107), other oral antipsychotics (paliperidone palmitate group, n = 199; RLAI group, n = 203), or no antipsychotic (paliperidone palmitate group, n = 56; RLAI group, n = 56). Mean PANSS total scores improved significantly at end point across all subgroups (mean change from baseline ranged from -17.5 to -19.5, all P < 0.0001). Clinical Global Impression-Severity and Personal and Social Performance scale measures also significantly improved from baseline (all P < 0.0001).ConclusionTreatment with paliperidone palmitate or RLAI resulted in a significant reduction in the symptoms of schizophrenia irrespective of previous recent treatment with oral risperidone only or other oral antipsychotics. For subjects who had previously received oral risperidone only, the difference in formulation was the main change in the intervention because the molecule delivered remained the same or similar. These data support the contribution of a long-acting formulation to improving the treatment response and suggest that nonadherence may be a significant contributor to inadequate efficacy of oral formulations in subjects with schizophrenia.

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Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials.

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Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials.

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