Long-term Treatment Of Adults Research Articles

Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis

Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. UK National Institute for Health Research Oxford Health Biomedical Research Centre.

State-of-the-Art 2019 on Gene Therapy for Phenylketonuria.

Phenylketonuria (PKU) is considered to be a paradigm for a monogenic metabolic disorder but was never thought to be a primary application for human gene therapy due to established alternative treatment. However, somewhat unanticipated improvement in neuropsychiatric outcome upon long-term treatment of adults with PKU with enzyme substitution therapy might slowly change this assumption. In parallel, PKU was for a long time considered to be an excellent test system for experimental gene therapy of a Mendelian autosomal recessive defect of the liver due to an outstanding mouse model and the easy to analyze and well-defined therapeutic end point, that is, blood l-phenylalanine concentration. Lifelong treatment by targeting the mouse liver (or skeletal muscle) was achieved using different approaches, including (1) recombinant adeno-associated viral (rAAV) or nonviral naked DNA vector-based gene addition, (2) genome editing using base editors delivered by rAAV vectors, and (3) by delivering rAAVs for promoter-less insertion of the PAH-cDNA into the Pah locus. In this article we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.

PTH-197 Long-Term Efficacy of Lubiprostone Demonstrated in Patients with Constipation Regardless of age, Gender or Race

IntroductionConstipation affects millions globally and may require chronic treatment. In 24- and 48-week trials, lubiprostone demonstrated safety and efficacy in long-term treatment of adults with chronic idiopathic constipation. Analyses of...

Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary

Objective:Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS).Design:A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials.Setting:Placebo-controlled, active-comparator, short- and long-term studies were reviewed.Participants:Adult (≥18 years) patients with MDD.Measurements:Effect sizes for continuous outcome (change from baseline to endpoint) and categorical outcome (response and remission rates) were calculated using the primary measures of 17-item Hamilton Rating Scale for Depression (HAMD-17) or Montgomery–Åsberg Depression Rating Scale (MADRS) total score. The Brief Pain Inventory and Visual Analogue Scales were used to assess improvements in PPS. Glass estimation method was used to calculate effect sizes, and numbers needed to treat (NNT) were calculated based on HAMD-17 and MADRS total scores for remission and response rates. Safety data were examined via the incidence of treatment-emergent adverse events and by mean changes in vital-sign measures.Results:Treatment with duloxetine was associated with small-to-moderate effect sizes in the range of 0.12 to 0.72 for response rate and 0.07 to 0.65 for remission rate. NNTs were in the range of 3 to 16 for response and 3 to 29 for remission. Statistically significant improvements (p≤0.05) were observed in duloxetine-treated patients compared to placebo-treated patients in PPS and quality of life. The safety profile of the 60-mg dose was consistent with duloxetine labeling, with the most commonly observed significant adverse events being nausea, dry mouth, diarrhea, dizziness, constipation, fatigue, and decreased appetite.Conclusion:These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective short- and long-term treatment for adults with MDD. The evidence of the independent analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with PPS associated with depression. This review is limited by the fact that it included randomized clinical trials with different study designs. Furthermore, data from randomized controlled trials may not generalize well to real clinical practice.

Sustained Hemostatic Platelet Counts in Adults with Immune Thrombocytopenia (ITP) Following Cessation of Treatment with the TPO Receptor Agonist Romiplostim: Report of 9 Cases,

Abstract 3281▪▪This icon denotes a clinically relevant abstract Background:While romiplostim is often perceived as a long-term treatment for adults with chronic ITP, previous data suggest that some patients can maintain hemostatic platelet counts when romiplostim is permanently discontinued, as occurred in 7 of 83 romiplostim-treated patients in the pivotal trials (Kuter et al, Lancet 2008) and as presented at the 2011 EHA meeting (Newland et al, 2011). Methods:We describe 9 patients from an open-label extension study (N = 291, Bussel et al, Blood 2009) who had ITP of various durations unresponsive to treatments such as splenectomy, corticosteroids, IVIg, anti-D, danazol, azathioprine, and rituximab. Romiplostim was administered at the same dose as in the previous study or at 1 μg/kg (if patients had previously received placebo) and adjusted by no more than 1 μg/kg weekly to maintain platelet counts at 50–200×109/L. These patients were selected for this report because romiplostim was discontinued and hemostatic platelet counts maintained for at least 6 months. Results:In these cases, patients had ITP ranging in duration from 0.1 to 5.5 years and between 2 and 5 prior ITP therapies before entering romiplostim clinical trials (Table). The duration over which romiplostim was received in these cases (previous study and extension study combined) ranged from 37 to 139 weeks. No clinically significant bleeding (grade ≥3) was observed with romiplostim in these patients during the initial studies; during the open-label extension, epistaxis in Week 10 and gastrointestinal hemorrhage in Week 18 were reported for Case 6. Examination of these 9 cases indicates that there are no factors that appear to predict which patients, after discontinuing romiplostim, will achieve hemostatic platelet counts off treatment. Of note, as this was a post hoc analysis and not a prespecified endpoint, there may be other cases in which hemostatic platelet counts were maintained without romiplostim treatment. Summary/conclusions:Dose adjustment rules allow romiplostim to be discontinued when appropriate. These case reports indicate that some patients may not require romiplostim indefinitely. In the absence of other ITP treatments (e.g., immunosuppressive therapies), hemostatic platelet counts can be maintained in certain cases after cessation of romiplostim. We believe that more such cases will become known, allowing us to gain greater insights into which ITP patients are able to discontinue romiplostim and to the relationship to the natural history of ITP and possible remission. Potential mechanisms for this phenomenon should be explored, including what role is played by the improvement of T-regulatory cell function in the presence of hemostatic platelet counts (Bao et al, Blood 2010).Table Patient dataPatient123456789Age (yrs)435154467929505138SexMMFFFMFFFITP duration (years)10.11.30.60.63.35.54.2NA0.8Splenectomy–Yes–––YesYes–YesPrior ITP therapies2232543NA2Baseline plt count216132358951113424938Romiplostim starting dose1621215111Range romiplostim dose11–651–2511–452–155151–351–8Romiplostim over X weeks this study (parent study)3 (52)21 (16)23 (52)23 (52)41 (24)91 (24)105 (24)117 (6)139 (0)Plt range on romiplostim this study3161–25532–809134–63883–26711–7469–74930–43731–7364–849Plt count before last romiplostim dose233380272267313303437309471Weeks after romiplostim discontinued4772636411661258815347Plt range after romiplostim discontinued94–174148–511213–41176–48797–496262–61172–255225–467125–366Post–study follow–up6Plt stableNANANA18 m later required ITP Rx7Plt stablePlt stableNAPlt stablePlt, platelet, NA = not available. Plt counts, × 109/L; romiplostim dose, μg/kg/week.1At initial romiplostim trial2For the latter part of the extension, baseline platelet count could be of any level.3Platelet counts for the 4 weeks after IVIg (as occurred with patients 8 and 9) were excluded.4Platelet counts >50×109/L lasted until the end of the study for all patients.5Romiplostim treatment was not continuous in these patients.6Where follow-up was available718 months post-study, this patient developed epistaxis, bruising, and petechiae, for which she received prednisone for 1 week. Romiplostim was also restarted. [Display omitted] Disclosures:Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Rodeghiero:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Suppremol: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kessler:Amgen: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Griffols: Consultancy, Research Funding. Terriou:Amgen: Honoraria; GSK: Honoraria. Stasi:GSK: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Suppremol: Consultancy, Honoraria; Nycomed: Honoraria; Bayer: Honoraria; Baxter: Honoraria. Chang:Amgen: Employment, Equity Ownership. Jun:Amgen: Employment, Equity Ownership.

Milnacipran and venlafaxine at flexible doses (up to 200 mg/day) in the outpatient treatment of adults with moderate-to-severe major depressive disorder: a 24-week randomized, double-blind exploratory study

The objective of this exploratory, multicenter, randomized, double-blind study, was to evaluate the efficacy and safety/tolerability of milnacipran and venlafaxine administered at flexible doses (100, 150 or 200 mg/day, bid administration) for 24 weeks (including 4 weeks up titration period) in the outpatient treatment of adults presenting with a moderate or severe episode of major depressive disorder (MDD) without high suicidal risk (MINI-DSM IV-TR). Of the 195 patients included, 134 (68.7%) completed the study. At baseline the two groups were similar, except there was a higher proportion of patients whose episode was severe-DSM IV in the milnacipran group (63.3% versus 54.0% in the venlafaxine group). The initial MADRS score (mean 31.0) decreased progressively during the study, and this decrease was in the two treatment groups (n = 177: 90 milnacipran; 87 venlafaxine) at week 24 (observed case/OC, mean change -23.1 milnacipran; -22.4 venlafaxine). The rate of MADRS response (reduction >/= 50%) at week 8 and week 24-last observation carried forward/LOCF was similar in the two groups (week 8: 64.4% milnacipran; 65.5% venlafaxine; week 24: 70% milnacipran; 77% venlafaxine), as was the rate of MADRS remission (score </= 10) (week 8: 42.2% milnacipran; 42.5% venlafaxine; week 24: 52.2% milnacipran; 62.1% venlafaxine). In both groups, the most common adverse events were: nausea, dizziness, headache, hyperhidrosis and, in males, genito-urinary problems. The overall safety/tolerability and efficacy profiles of milnacipran and venlafaxine administered at flexible dosages (up to 200 mg/day) were similar in the long term treatment of adults during episodes of MDD in an outpatient setting.

Milnacipran et venlafaxine à posologie flexible (jusqu’à 200 mg/j) dans le traitement ambulatoire des épisodes dépressifs majeurs modérés à sévères de l’adulte : étude exploratoire de 24 semaines, randomisée en double insu

Resume L’objectif de cet essai exploratoire multicentrique, randomise, en double insu, etait d’evaluer l’efficacite et la tolerance du milnacipran (MLN) et de la venlafaxine (VLF) administres a posologie flexible (100, 150 ou 200 mg/j en deux prises journalieres) pendant 24 semaines (dont quatre semaines de titration croissante) dans le traitement ambulatoire de l’adulte presentant un episode depressif majeur modere a severe sans risque suicidaire eleve (MINI–DSM IV-TR). Parmi les 195 patients inclus, 134 (68,7 %) ont complete l’essai. Les caracteristiques basales des deux groupes etaient similaires hormis une proportion sensiblement superieure de patients sous MLN presentant un episode severe-DSM IV (63,3 % versus 54,0 % de patients sous VLF). Le score MADRS initial (moyenne : 31,0) a progressivement diminue et de facon superposable dans les deux groupes analyses (n = 177 : 90/MLN, 87/VLF) jusqu’a semaine 24 (S24-OC ; moyenne : –23,1/MLN ; –22,4/VLF). Les taux de reponse MADRS (reduction ≥ 50 %) a S8 et S24-last-observation-carried-forward (LOCF) etaient similaires dans les deux groupes (S8 : 64,4 %/MLN, 65,5 %/VLF ; S24 : 70 %/MLN, 77 %/VLF), ainsi que les taux de remission MADRS (score ≤ 10) (S8 : 42,2 %/MLN, 42,5 %/VLF ; S24 : 52,2 %/MLN, 62,1 %/VLF). Dans les deux groupes, les evenements indesirables les plus frequents etaient nausees, sensation vertigineuse, cephalees, hyperhidrose et troubles urogenitaux masculins. MLN et VLF administres a posologie flexible (jusqu’a 200 mg/j) ont montre des profils d’efficacite et de tolerance globalement similaires dans le traitement ambulatoire au long terme de l’episode depressif majeur de l’adulte.

0466 RESULTS FROM A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF OLANZAPINE IN ADOLESCENTS WITH SCHIZOPHRENIA

0466 RESULTS FROM A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF OLANZAPINE IN ADOLESCENTS WITH SCHIZOPHRENIA

P.2.086 Neuropeptide Y in plasma during physical exercise test in patients with major depressive disorder

P.2.086 Neuropeptide Y in plasma during physical exercise test in patients with major depressive disorder