A network meta-analysis of the dose–response effects of lurasidone on acute schizophrenia

AbstractWe compared the efficacy, safety, and acceptability of lurasidone at different doses to establish the dose–response relationships of lurasidone therapeutic and adverse effects in acute schizophrenia. Included trials were 4- to 16-week, fixed-dose, randomized controlled trials of lurasidone in adults with acute schizophrenia. Different doses of lurasidone, other antipsychotics, and placebo were considered as independent treatments. Apart from all-cause dropout rates, four therapeutic and four adverse outcomes were included in the frequentist network meta-analysis (NMA). Lurasidone 160, 120, 80, 40, and 20 mg/day were studied in ten trials of 3,366 adults with schizophrenia exacerbation. Lurasidone 160 mg/day reduced Positive and Negative Syndrome Scale (PANSS) total scores significantly more than lurasidone 120, 80, 40, and 20 mg/day (mean differences = − 7.63, − 7.04, − 8.83, and − 12.25, respectively). All-cause dropout rates were significantly lower in participants receiving lurasidone 160 mg/day and 80 mg/day compared with those taking placebo. The half-maximal effective doses of lurasidone for PANSS total, PANSS positive, and MADRS score reductions were higher than 80 mg/day. The confidence of all NMA estimates was low or very low. Lurasidone 160 mg/day is currently the most efficacious and acceptable dose for acute schizophrenia. Its maximal effective doses may be higher than 160 mg/day.

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109 Comparative Efficacy and Tolerability of Lurasidone Versus Other Oral Atypical Antipsychotics for Pediatric Schizophrenia: A Network Meta Analysis

CNS Spectrums ◽

10.1017/s1092852918000093 ◽

2018 ◽

Vol 23 (1) ◽

pp. 70-71

Author(s):

Celso Arango ◽

Daisy Ng-Mak ◽

Elaine Finn ◽

Aidan Byrne ◽

Krithika Rajagopalan ◽

...

Keyword(s):

Weight Gain ◽

Atypical Antipsychotics ◽

Meta Analysis ◽

Credible Interval ◽

Similar Efficacy ◽

Binary Outcomes ◽

Trial Duration ◽

Study Objective ◽

Syndrome Scale ◽

Mean Differences

AbstractStudy ObjectiveThis analysis assessed the relative efficacy and tolerability of lurasidone versus other atypical antipsychotics in the treatment of pediatricschizophrenia.MethodsA systematic literature review identified 13 randomized-controlled trials for the treatment of pediatric schizophrenia. A Bayesian network meta-analysis compared the efficacy and tolerability of the following atypical antipsychotics: aripiprazole, asenapine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, andziprasidone. Patients were 7-17 years old and trial duration ranged from 6-12 weeks. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause treatment discontinuation, and extrapyramidal symptoms. Results from the fixed effect models were reported as mean differences for continuous outcomes and odds ratios for binary outcomes; each with a 95% credible interval.ResultsLurasidone had significantly greater improvement compared with placebo for PANSS (-7.95 [-11.76, -4.16]) and CGI-S (-0.44 [-0.67, -0.22]), but did not differ from comparators. The differences in weight gain for lurasidone relative to comparators were as follows: clozapine (-3.81kg [-8.03, 0.42]), olanzapine (-3.62kg [-4.84, -2.41]), quetiapine (-2.13kg [-3.20, -1.08]), risperidone (-1.16kg [-2.14, -0.17]), asenapine (-0.98kg [-1.71, -0.24]), paliperidone (-0.85kg [-1.57, -0.14]), aripiprazole (-0.15kg [-0.88, 0.58]), and ziprasidone (0.38kg [-0.49, 1.24]); all were statistically significant except for clozapine, aripiprazole, and ziprasidone. Rates of all-cause discontinuation andextrapyramidal symptoms were similar for lurasidone and comparators, except aripiprazole and paliperidone, which had higher rates of all-cause discontinuation.ConclusionsIn this network meta-analysis of atypical antipsychotics for the treatment of adolescent schizophrenia, lurasidone was associated with similar efficacy, but less weight gain than active comparators.Funding AcknowledgementsThis study was funded by Sunovion Pharmaceuticals Inc.

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Effects of Aerobic Exercise and Mind-Body Exercise in Parkinson’s Disease: A Mixed-Treatment Comparison Analysis

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.739115 ◽

2021 ◽

Vol 13 ◽

Author(s):

Chunxiao Wu ◽

Yingshan Xu ◽

Hongji Guo ◽

Chunzhi Tang ◽

Dongfeng Chen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Activities Of Daily Living ◽

Dose Response ◽

Daily Living ◽

Meta Analysis ◽

Response Analysis ◽

Motor Score ◽

Mean Differences ◽

Updrs Motor Score

Background/Objectives: Aerobic exercise and mind-body exercise, are vital for improving motor and non-motor functional performance of Parkinson’s disease (PD). However, evidence-based recommendations on which type of exercise is most suitable for each individual are still lacking. Therefore, we conduct a network meta-analysis to assess the relative efficacy of aerobic and mind-body exercise on motor function and non-motor symptoms in Parkinson’s disease and to determine which of these therapies are the most suitable.Design: A network meta-analysis and dose-response analysis.Setting and Participants: Medline, Embase (all via Ovid), and the Cochrane Central Register of Controlled Trials were comprehensively searched for related trials through April 2021.Measurements: Study quality was evaluated using the Cochrane Risk of Bias Tool. The effect sizes of continuous outcomes were calculated using mean differences (MDs) or standardized mean differences (SMDs). A network meta-analysis with a frequentist approach was conducted to estimate the efficacy and probability rankings of the therapies. The dose-response relationship was determined based on metaregression and SUCRA.Results: Fifty-two trials with 1971 patients evaluating six different therapies were identified. For the UPDRS-motor score and TUG score, yoga all ranked highest (SUCRA = 92.8%, 92.6%, respectively). The SUCRA indicated that walking may best improve the BBS score (SUCRA = 90.2%). Depression, cognitive and activities of daily living scores were significantly improved by yoga (SUCRA: 86.3, 95.1, and 79.5%, respectively). In the dose-response analysis, 60-min sessions, two times a week might be the most suitable dose of yoga for reducing the UPDRS-motor score of PD patients.Conclusion: Yoga and walking are important options for increasing functional mobility and balance function, and yoga might be particularly effective for decreasing depressive symptoms and cognitive impairment and improving activities of daily living in PD. The potential optimal dose of yoga for enhancing motor ability in PD patients is 60-min sessions, two times a week.Registration: PROSPERO CRD42021224823.

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Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of randomized controlled acute phase trials

npj Schizophrenia ◽

10.1038/s41537-021-00171-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Michel Sabe ◽

Nan Zhao ◽

Alessio Crippa ◽

Stefan Kaiser

Keyword(s):

Acute Phase ◽

Dose Response ◽

Negative Symptoms ◽

Meta Analysis ◽

Positive Symptoms ◽

Response Curves ◽

Randomized Controlled ◽

Effective Doses ◽

Dose Response Curves ◽

Long Acting

AbstractDetermining the optimal antipsychotic target dose in acute phase treatment is of high clinical relevance. The effect of antipsychotics on negative symptoms should be taken into account because patients will often continue on the treatment received in the acute phase. Therefore, we conducted a formal dose-response meta-analysis of negative symptoms and positive symptoms based on a systematic review of fixed-dose randomized controlled trials (RCTs) that examined the effectiveness of antipsychotics for the acute exacerbation of schizophrenia. Forty RCTs included a total of 15,689 patients. The 95% effective doses per day for the 13 antipsychotics included and 3 long acting were mostly different for negative and positive symptoms: amisulpride (481 mg, 690.6 mg); aripiprazole (11.9 mg, 11 mg); asenapine (7.61 mg, 5.66 mg); brexpiprazole (2.1 mg, 4 mg); cariprazine (4 mg, 6.51 mg); haloperidol (6.34 mg, 7.36 mg); lurasidone (58.2 mg, 86.3 mg); olanzapine (15.5 mg, 9.52 mg); olanzapine long-acting injection (15.7 mg, 13.5 mg); paliperidone (7.2 mg, 7 mg); paliperidone long-acting injection (7.5 mg, 5.9 mg); quetiapine instant-release (264.2 mg, 316.5 mg); quetiapine extended-release (774 mg, 707.2 mg); risperidone (7.5 mg, 7.7 mg); risperidone long-acting injection (5.13 mg, 6.7 mg); sertindole (13.5 mg, 16.3 mg); and ziprasidone (71.6 mg, 152.6 mg). The shape of the dose-response curves varied across different drugs with most drugs showing a plateau at higher doses. Most dose-response curves suggested that the near-maximum effective doses could be in the lower-to-medium range of the licensed dose. Additional RCTs are necessary to establish the optimal dose.

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Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa063 ◽

2020 ◽

Vol 46 (6) ◽

pp. 1439-1458

Author(s):

Hiroyoshi Takeuchi ◽

Nicole E MacKenzie ◽

Dominic Samaroo ◽

Ofer Agid ◽

Gary Remington ◽

...

Keyword(s):

Side Effects ◽

Meta Analysis ◽

Positive Symptom ◽

Fixed Dose ◽

Double Blind ◽

Acute Schizophrenia ◽

Second Generation Antipsychotics ◽

Oral Antipsychotic ◽

Relationship Of ◽

Higher Doses

Abstract Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose–response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.

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Association of postoperative fluid overload with adverse outcomes after congenital heart surgery: a systematic review and dose-response meta-analysis

Pediatric Nephrology ◽

10.1007/s00467-020-04489-4 ◽

2020 ◽

Vol 35 (6) ◽

pp. 1109-1119 ◽

Cited By ~ 2

Author(s):

Ioannis Bellos ◽

Dimitrios C. Iliopoulos ◽

Despina N. Perrea

Keyword(s):

Systematic Review ◽

Dose Response ◽

Congenital Heart ◽

Heart Surgery ◽

Fluid Overload ◽

Meta Analysis ◽

Congenital Heart Surgery ◽

Adverse Outcomes

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Exploring the appropriate dose of nebulized hypertonic saline for bronchiolitis: a dose–response meta-analysis

Journal of Investigative Medicine ◽

10.1136/jim-2021-001947 ◽

2021 ◽

pp. jim-2021-001947

Author(s):

Jilei Lin ◽

Yin Zhang ◽

Anchao Song ◽

Linyan Ying ◽

Jihong Dai

Keyword(s):

Hypertonic Saline ◽

Dose Response ◽

Sequential Analysis ◽

Meta Analysis ◽

Trial Sequential Analysis ◽

Controlled Trials ◽

Cochrane Central Register ◽

Eligibility Criteria ◽

Significant Difference ◽

Different Doses

Nebulized hypertonic saline (HS) has gathered increasing attention in bronchiolitis. This study aims to evaluate the relationship between the dose of nebulized HS and the effects on bronchiolitis. Five electronic databases—PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and ISRCTN—were searched until May 2021. Randomized controlled trials (RCTs) that investigated the effect of HS on bronchiolitis were included. A total of 35 RCTs met the eligibility criteria. HS nebulization may shorten the length of stay (LOS) in hospital (mean difference −0.47, 95% CI −0.71 to –0.23) and improve the 24-hour, 48-hour, and 72-hour Clinical Severe Score (CSS) in children with bronchiolitis. The results showed that there was no significant difference between 3% HS and the higher doses (>3%) of HS in LOS and 24-hour CSS. Although the dose–response meta-analysis found that there may be a linear relationship between different doses and effects, the slope of the linear model changed with different included studies. Besides, HS nebulization could reduce the rate of hospitalization of children with bronchiolitis (risk ratio 0.88, 95% CI 0.78 to 0.98), while the trial sequential analysis indicated the evidence may be insufficient and potentially false positive. This study showed that nebulized HS is an effective and safe therapy for bronchiolitis. More studies are necessary to be conducted to evaluate the effects of different doses of HS on bronchiolitis.

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A Network Meta-Analysis of the Efficacy and Safety of Empagliflozin at Different Doses in Patients with Diabetes Mellitus Based on Randomized Controlled Trials

10.21203/rs.3.rs-32579/v1 ◽

2020 ◽

Author(s):

Qian Wu ◽

Chen Liao ◽

Mengyu He ◽

Can Li ◽

Fang Zou ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Dose Response ◽

Meta Analysis ◽

Cochrane Library ◽

Pharmacokinetic Parameters ◽

Controlled Trials ◽

Low Doses ◽

Randomized Controlled ◽

High Doses ◽

Different Doses

Abstract Background and objective: As an oral hypoglycemic drug that significantly reduces cardiovascular risk, empagliflozin is used in patients with type 2 diabetes. However, the dosage and administration of empagliflozin are still controversial clinically. To determine the appropriate treatment, we performed this network meta-analysis.Methods: We identified randomized controlled trials (RCTs) about empagliflozin from databases including PubMed, Ovid MEDLINE, Embase, ScienceDirect, Web of Science, the Cochrane Library, Scopus and Google Scholar. We analyzed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses.Results: We identified 8264 articles, of which 26 RCTs with 11796 patients were included. Regarding hemoglobin A1c (HbA1c ) and fasting plasma glucose (FPG), high doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 2.5 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1 > 2.5 > 5 > 25 > 10 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships .Conclusions: High doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses. More RCTs exploring unconventional doses are needed to confirm these conclusions.

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Dose-Dependent Efficacy of Aripiprazole in Treating Patients With Schizophrenia or Schizoaffective Disorder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.717715 ◽

2021 ◽

Vol 12 ◽

Author(s):

Li Qian ◽

Liao Xuemei ◽

Li Jitao ◽

Su Yun'Ai ◽

Si Tianmei

Keyword(s):

Side Effects ◽

Dose Group ◽

Low Dose ◽

Meta Analysis ◽

High Dose Group ◽

Controlled Trials ◽

High Dose ◽

Randomized Controlled ◽

Syndrome Scale ◽

Mean Differences

Purpose: To compare the efficacy and tolerability of different administration strategies of aripiprazole.Methods: We searched MEDLINE, EMBASE, the Cochrane Central, Web of Science, China National Knowledge Infrastructure(CNKI), and Wanfang Data Knowledge Service Platform(Wanfang) for randomized controlled trials (RCTs) of aripiprazole, using the terms: (aripiprazole) AND (schizophr* OR schizoaff*) AND (“syndrome scale” OR PANSS) AND (clini* OR trial). We retrieved study design, participant characteristics, comparison groups, and outcomes from each study.Results: In total, nine RCTs were selected for meta-analysis, which covered ~1,187 participants. We defined two treatment groups that represent different treatment strategies: (1) the high-dose group (the high-dose strategy) rapidly increased to doses higher than 15 mg/day in 2 weeks or began with doses higher than 15 mg/day, otherwise the group was defined as (2) the low-dose group (the low-dose strategy). If the initial or target doses of aripiprazole in a study were all higher than 15 mg/day, the high- and low-dose groups were created based on the relative level of the dose. The high-dose group showed significantly greater reductions in Positive and Negative Syndrome Scale (PANSS) total scores (standardized mean differences = −8.31, 95% confidence interval [CI] = −16.48, −0.13; P < 0.01; I2 = 96%) than the low-dose group. The high-dose group showed superior effects compared with the low-dose group in long-term studies (more than 8 weeks) (standardized mean differences = −13.81, 95% CI = −25.07, −2.55; P < 0.01; I2 = 96%). With exception of somnolence, we did not find significant differences in side effects or discontinuation due to adverse events. Sensitivity analyses produced similar results.Conclusion: The high-dose treatment strategy of aripiprazole for patients with schizophrenia or schizoaffective disorder may bring more benefits without obvious side effects.

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Efficacy, safety, and tolerability of vortioxetine for the treatment of major depressive disorder in patients aged 55 years or older

CNS Spectrums ◽

10.1017/s1092852916000626 ◽

2016 ◽

Vol 22 (4) ◽

pp. 348-362 ◽

Cited By ~ 7

Author(s):

George G. Nomikos ◽

Dapo Tomori ◽

Wei Zhong ◽

John Affinito ◽

William Palo

Keyword(s):

Body Weight ◽

Major Depressive Disorder ◽

Depressive Disorder ◽

Rating Scale ◽

Liver Enzymes ◽

Meta Analysis ◽

Vital Signs ◽

Fixed Dose ◽

Major Depressive ◽

Mean Differences

ObjectiveThese post hoc analyses evaluate the efficacy, safety, and tolerability of vortioxetine versus placebo in patients aged ≥55 years with major depressive disorder (MDD).MethodsStudy-level efficacy data from 12 short-term, fixed-dose, randomized, placebo-controlled trials of vortioxetine 5–20 mg/day were assessed using a random-effects meta-analysis. Adverse events (AEs), vital signs, ECG values, liver enzymes, and body weight were pooled from the same studies. Patients had baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total scores ranging from 22–30.Results1508 patients (mean age=62.4 years; range, 55–88 years) were included. Mean differences from placebo in change from baseline to study end (6/8 weeks) in MADRS were –2.56 (5 mg, n=324, P=0.035), –2.87 (10 mg, n=222, P=0.007), –1.32 (15 mg, n=90, P=NS), and –4.65 (20 mg, n=165, P=0.012). Odds ratios for response versus placebo were 1.6 (5 mg, P=NS), 1.8 (10 mg, P=0.002), 1.2 (15 mg, P=NS), and 2.5 (20 mg, P<0.001), and for remission versus placebo were 1.5 (5 mg, P=NS), 1.5 (10 mg, P=NS), 1.4 (15 mg, P=NS), and 2.7 (20 mg, P=0.001). The proportion of patients with AEs for placebo and vortioxetine 5–20 mg was 61.5% and 62.3%, respectively, with no increase at increased doses. Vortioxetine demonstrated a placebo-level incidence of serious AEs (1.2%). AEs occurring in ≥5% of any treatment group were nausea, headache, diarrhea, dizziness, dry mouth, constipation, fatigue, vomiting, and anxiety. No clinically significant mean changes in vital signs, ECG values, liver enzymes, or body weight emerged during treatment.ConclusionVortioxetine 5–20 mg/day is efficacious and well tolerated in MDD patients aged ≥55 years, a group that is often comorbid with other conditions and treated with other medications.

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