Add-on Studies Research Articles

New treatment perspectives for negative symptoms

AbstractIntroductionPersistent negative symptoms of schizophrenia are generally considered difficult to treat or treatment resistant. A large number of investigational drugs developed and or tested for the treatment of persistent negative symptoms failed to show efficacy leading to pessimism in treatment and disinvestment in treatment research of negative symptoms.Objectives1. To demonstrate, that available treatment methods – both pharmacological and non-pharmacological - are in fact effective for the treatment of negative symptoms of schizophrenia 2. To shortly summarize new drug research in this field.MethodReview of research data.ResultsThe overall estimate for the placebo effect had a medium effect size, with a Cohen’s d value of 0.6444 (SE = 0.091).1 The estimates for the placebo effect were similar in the add-on and monotherapy studies. Amisulprid was superior to placebo, cariprazine was superior to risperidone, and “direct comparisons of antipsychotics in patients with predominant negative symptoms indicated no significant difference between amisulpride and olanzapine and between asenapine and olanzapine…”2. Various nonpharmacological interventions improved negative symptoms in randomized controlled trials relative to treatment as usual (e.g. social skills training, music therapy, non-invasive brain stimulation, mindfulness, and exercise-based interventions) 3 There is a progress in research with non-dopaminergic agents for the treatment of negative symptoms (e.g. pimavanserin, roluperidon, ulotaront).Conclusions For medication classes other than antipsychotics and antidepressants, we found no reliable support for evidence-based recommendations for using these agents in the treatment of negative symptoms in clinical practice. Effect sizes for psychosocial interventions range from small to moderate. The use of placebo has shown a clinically significant positive effect on negative symptoms, a finding that warrants further research and provides a sense of optimism regarding potential therapeutic benefits.1.Czobor, P., Kakuszi, B. and Bitter, I., 2022. Placebo response in trials of negative symptoms in schizophrenia: a critical reassessment of the evidence. Schizophrenia Bulletin, 48(6), pp.1228-1240. 2. Czobor, P., Bitter I. Pharmacologic treatment of negative symptoms: Focus on efficacy. In: Bitter I. (ed): Managing Negative Symptoms of Schizophrenia, Oxford University Press, 2020, p. 672.Savill, M. Psychosocial/non-pharmacologic treatment of negative symptoms: focus on efficacy. In: Bitter I. (ed): Managing Negative Symptoms of Schizophrenia, Oxford University Press, 2020, p. 87Disclosure of InterestNone Declared

Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia: a national, prospective, longitudinal study in the Netherlands

ObjectivesHealth-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse,...

A review of interventional schizophrenia trials registered in clinical trials registry of India

Background: The current therapies for schizophrenia are targeted at reducing the severity of symptoms and they do not cure the disease. The research in this field is going on for many years. The present study was designed to access the current status of interventional studies conducted in schizophrenia based on studies registered in the CTRI. Methods: Interventional studies for schizophrenia registered on CTRI from 2007 to May 2022 were reviewed and analysed, using the keyword “schizophrenia”. Parameters such as number of studies, year wise distribution of the studies registered, status of the studies at the time of analysis, types of study designs, randomization, blinding, geographical distribution, type of intervention. Results: Out of 42952 studies registered with CTRI from 2007 to May 2022, 323 studies exclusively involved schizophrenia which accounts for only 0.75% of the total studies. 206 were interventional studies. Among the interventional studies 188 were randomized and 87 were blinded. Of all the interventional studies 141(68.4%) involved pharmacological interventions (Allopathy), 53 (25.7%) were non drug interventions, the rest were AYUSH. Of the 141 studies involving pharmacological interventions 28 were comparative studies with active control, 23 were addon studies, 14 were single arm efficacy and safety studies and 76 were BA/BE studies. Conclusions: The study showed a rise in schizophrenia interventional study registries in the last 5 years. However, it highlighted the need to conduct more comparative studies with active control or efficacy and safety studies rather than BA/BE studies, in order to propose better alternatives to the existing therapy.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2011, and most recently updated in 2019. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 13 July 2021) on 15 July 2021. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, a third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome of 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate whilst another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and rated the evidence as very low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Placebo Response in Trials of Negative Symptoms in Schizophrenia: A Critical Reassessment of the Evidence.

Summarizing evidence from clinical trials of patients with schizophrenia with predominant or prominent negative symptoms (NS), a prior meta-analysis reported a large placebo effect in negative symptoms (Cohen's d = 2.909). Assuming that such an effect was clinically not plausible, we performed a critical re-assessment and an update of the previous results with newly available data from add-on and monotherapy studies. Random-effect meta/regression analysis of trials that focused on predominant or prominent NS; and adopted a double-blind, randomized, placebo-controlled design. The final pooled meta-analytic database, based on the available add-on and monotherapy studies combined, included 24 publications containing data on a total of 25 studies (21 add-on, 4 monotherapy). The pooled overall estimate for the placebo effect from the primary analysis for all included studies had a medium effect size, with a Cohen's d value of 0.6444 (SE = 0.091). The estimates were similar in the add-on and monotherapy studies. Meta-regression indicated that the high placebo response was significantly associated with clinical trial characteristics, including the high ratio of patients assigned to active vs. placebo treatment and short trial duration. These results represent a major downward correction for a current effect size estimate of the placebo response in the negative symptoms of schizophrenia. Our findings also pinpoint certain clinical trial characteristics, which may serve as important predictors of the placebo response. The knowledge of these factors can have important implications for drug development and trial design for new drugs for negative symptoms of schizophrenia.

Third-Generation Antiseizure Medications for Adjunctive Treatment of Focal-Onset Seizures in Adults: A Systematic Review and Network Meta-analysis.

BackgroundBrivaracetam (BRV), cenobamate (CNB), eslicarbazepine acetate (ESL), lacosamide (LCM) and perampanel (PER) are antiseizure medications (ASMs) approved for adjunctive treatment of focal-onset seizures. So far, no randomised controlled trial directly compared the efficacy and safety of these drugs.ObjectiveWe estimated the comparative efficacy and safety of these ASMs for the treatment of focal-onset seizures in adults with epilepsy using a network meta-analysis (NMA).MethodsWe systematically searched (June week 4, 2021) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov). There were no date limitations or language restrictions. Randomised, double-blinded, controlled, parallel-group, add-on studies that compared oral BRV, CNB, ESL, LCM, and PER versus any comparator over maintenance periods of at least 12 weeks and included adult patients with focal seizures uncontrolled by concomitant ASMs were identified. The efficacy outcomes were the proportions of patients with ≥ 50% and 100% reduction in baseline seizure frequency during the maintenance period. The tolerability outcomes were the proportions of participants who experienced at least one treatment-emergent adverse event (TEAE) and experienced at least one TEAE leading to discontinuation. Effect sizes were estimated by network meta-analyses within a frequentist framework. The hierarchy of competing interventions was established using the surface under the cumulative ranking curve (SUCRA).ResultsSixteen trials (BRV: n = 3, CNB: n = 1, ESL: n = 4, LCM: n = 4, PER: n = 4) were included, overall enrolling 4507 patients randomised to add-on active treatments (BRV = 803, CNB = 221, ESL =9 90, LCM = 1104, and PER = 1389) and 2246 to add-on placebo. Cenobamate was associated with a higher rate of ≥ 50% seizure frequency reduction than BRV [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.11–3.66], ESL (OR 1.93, 95% CI 1.07–3.48), LCM (OR 1.86, 95% CI 1.04–3.32), and PER (OR 2.07, 95% CI 1.16–3.70). There was a not statistically significant trend favouring CNB over ESL, LCM and PER for the seizure freedom outcome. Brivaracetam (OR 0.61, 95% CI 0.44–0.86) and LCM (OR 0.60, 95% CI 0.40–0.88) were associated with a lower proportion of participants experiencing TEAEs compared to ESL, and patients treated with PER were associated with a higher risk to experience at least one TEAE (OR 1.42, 95% CI 1.02–1.96) than BRV. According to SUCRA, CNB had the greatest likelihood of being the best option for the ≥ 50% and 100% seizure frequency reduction, and BRV and LCM had the highest probabilities of being the best-tolerated treatments.ConclusionsCenobamate ranked best for efficacy, and BRV and LCM were best tolerated over the other comparators. Although NMAs cannot replace direct comparisons, they may support physicians in clinical decision making.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01661-4.

The Importance of Frequent Flyer Programs: An In-depth Analysis

This paper discusses the important roles of frequent flyer programs (FFPs) in the airline industry with an emphasis on FFPs as a tool for airline business development, a customer relationship management (CRM) tool, and an airline tool of highest return of investment among CRM initiatives. An FFP is a sort of loyalty program sponsored by an airline or a group of airlines that rewards regular passengers with extras and prizes to make flying with the airlines convenient. Thus, advantages and disadvantages of FFPs between airline businesses and passengers are critically discussed. The paper examined existing and recent literature reviews with some add-on case studies. Interestingly, FFPs can be both push and pull factors for airline competitiveness enhancement, analytically reviewed. All discussions presented has revealed that FFPs can be a forceful tool for creating airline competitiveness, depending on how the airline manage it professionally or not. It can be summed that if the airlines manage their FFPs effectively, they can retain their existing passengers and be able to keep the market share. Hence, the airline competitors cannot effortlessly enter to the selected market.

Improving Knowledge on Pathways to Functional Outcome in Schizophrenia: Main Results From the Italian Network for Research on Psychoses.

The identification of factors associated with functional outcome of subjects with schizophrenia is a great challenge in current research oriented to the personalization of care. The Italian Network for Research on Psychoses (NIRP) is a network of 26 university psychiatric clinics and/or mental health departments aimed to carry out multicenter research projects to improve the standards of prevention, diagnosis, and treatments of schizophrenia. The network has promoted 2 main studies, a cross-sectional one and a longitudinal one and seven “add-on” studies. The cross-sectional study of the network included 921 subjects with schizophrenia, 379 unaffected first-degree relatives of these patients, and 780 healthy controls. Results from this study documented that social and non-social cognition, functional capacity, negative symptoms, resilience, and family or social incentives strongly influence a measure of global functioning. The follow-up study included 618 patients from the original sample and has produced evidence of the key role of cognition, functional capacity, the experiential domain of negative symptoms, and everyday life skills in predicting functional outcome. The longitudinal study demonstrated that social cognition and the experiential domain of negative symptoms had an impact on interpersonal functioning, while non-social cognition had an impact on everyday life skills. Both non-social cognition and social cognition predicted work skills. The research question concerning the relationships of cognitive impairment and negative symptoms has been investigated with an innovative approach, using a structural equation model (SEM) and a network analysis. Both analyses demonstrated that only the experiential domain of negative symptoms had a distinct direct effect on functioning. The network analysis showed that expressive deficit was connected to functional capacity, as were social and non-social cognitive variables, and to disorganization. These findings were confirmed by the follow-up study. The add-on studies showed distinct electrophysiological correlates of the two negative symptom domains and the partial overlap between disorganization and neurocognitive impairment. Moreover, they identified and characterized a specific subgroup of patients suffering from schizophrenia with autism spectrum symptoms. The NIRP studies have implications for personalized management of patients with schizophrenia and highlight the need for a careful assessment of several domains rarely evaluated in clinical settings.

A snapshot of “real world” current neuro-oncology practice in ten UK centres participating in the Tessa Jowell BRAIN MATRIX platform study

Abstract Aims The TJBM Platform Study (https://www.birmingham.ac.uk/research/crctu/trials/brain-matrix) is a programme of work aimed at improving the knowledge of, and treatment for, glioma. The study will develop a backbone infrastructure for a molecular diagnostic pathway, particularly epigenetic classification and whole genome sequencing (WGS), and a data-repository of disease imaging, including real-time centralised Response Assessment in Neuro-Oncology (RANO) review, treatment and outcome data. Developed with the involvement of patients and relatives, patient reported outcome measures (PROMs), particularly quality of life assessment will be collected for patients. We present the feasibility data collected from the initial ten UK centres selected to participate in the TJBM study. This presents an opportunity to understand current local neuro-oncology practice, identify differences between services and chances to optimise these, bearing in mind the heterogeneity in our patient populations, staff and hospital facilities. Method Ten UK centres were selected to participate in the TJBM platform study, and each centre completed a multi-disciplinary feasibility questionnaire to facilitate participation and collaboration across the centres. Data were collected from hospital electronic MDT (Multi-Disciplinary Team) records, clinic letters, operative and imaging notes, MDT or personal experience. Continuous variables were reported using medians and ranges due to the non-normality of the data and categorical variables were reported as numbers and percentages. Tables and bar charts were generated to display relevant data. Analysis and plots were generated using Microsoft Excel sheets and SPSS (IBM) version 26. Results Work load Between 2016-2018 service provision redistribution reflects a trend towards higher volume centres. Overall, glioma workload within ten TJBM centres has remained stable (Figure 1). Imaging All TJBM centres have good access to imaging techniques and neuroradiology expertise, including relevant ‘advanced’ imaging. All have RANO capability, although not widely used clinically. Neurosurgery All centres have access to 5 ALA, perform awake craniotomy for language assessment and motor/sensory mapping are typically performed asleep, with subtle variation in techniques. Pathology Despite molecular analysis advances, current practice is limited to the evaluation of formalin embedded tissue by traditional morphology/ immuno-histochemical staining, with limited targeted testing of specific genetic changes (Figure 2). Clinical oncology Oncology treatments for glioma were as per NICE guidance with some minor local variation. The data has informed the development of the TJBM protocol, an overview of which will be presented (Figure 3). Conclusion Through systematic real-world data collection the TJBM platform study will provide a detailed understanding of practice within the UK, linked to molecular tumour genotype, treatment response outcome measures, and also regular quality of life assessments. Use of the platform infrastructure, will facilitate trials and add-on observational and biological studies to obtain rapid, efficient, and cost-effective data collection, and integrate findings with comprehensive molecular biological profiling and radiological features, thereby reducing the time and administrative burdens in trial delivery. This infrastructure will help establish a trial-competent network on which future research and collaborations can be based. Academic and industry partners will be able to use the TJBM platform through collaboration, overseen by a strong governance framework. This will maximise the opportunities and abilities to translate advances into trials and patient benefit.

Machine Learning-Based Flow Cytometry Diagnostics in Myelodysplastic Syndromes: Validation in the HOVON89 Clinical Trial (EudraCT 2008-002195-10)

Introduction Flow cytometry is a recommended tool in the diagnostic work-up of cytopenic patients suspected for myelodysplastic syndromes. Currently used flow cytometry scores rely on human assessment of dysplastic features in the bone marrow. Although proven useful, these methods are labor intensive and require a high level of expertise. Therefore, we previously developed a machine learning-based workflow for flow cytometry diagnostics in MDS by combining computational cell detection and a machine learning-classifier. This workflow outperformed traditional diagnostic scores with respect to accuracy (sensitivity 85-97%, specificity 93-97%), time investment (<30 seconds) and required materials (manuscript submitted). In the present study, we validated sensitivity of the workflow in a well-characterized clinical trial cohort (HOVON89 EudraCT 2008-002195-10) of lower risk MDS patients. Method Patient inclusion and characteristics Very low to intermediate risk MDS patients enrolled in the HOVON89 clinical trial (EudraCT 2008-002195-10) were included. 53 patients met the additional inclusion criteria, concerning written consent for add-on studies and availability of required flow cytometry data. Sample preparation Bone marrow samples were processed for flow cytometry analysis according to the European Leukemia Net guidelines. This study focused on the antibody combination optimized for assessment of myeloid progenitors and erythroid dysplasia (CD45, CD34, CD117, HLA-DR, CD71, CD36, CD105, CD33, sideward light scatter (SSC) and forward light scatter (FSC)). Machine learning-based workflow The machine learning-based workflow was developed in a prior study based on a reference cohort consisting of MDS patients without excess of blasts(n=67) and non-MDS cases (n=81) (Figure 1). MDS patients were diagnosed based on (cyto)morphology, cytogenetics and clinical follow-up. Non-MDS cases were patients with confirmed non-neoplastic cytopenias (n=69) and age-matched healthy individuals (n=12). Results In the validation cohort, the machine learning-based diagnostic workflow classified 49 out of 53 patients correctly, reaching a sensitivity of 92%. The workflow outperformed two currently used diagnostic tools for MDS flow cytometry, the Ogata score and integrated flow cytometry score (iFS). The former obtained 72% sensitivity (McNemar: p = 0.001) and the latter 83% sensitivity (McNemar: p = 0.06) in the validation cohort. Per patient, time required for automated analysis was less than 30 seconds. All four MDS patients that classified false negatively had a normal karyotype and (very) low risk disease according to the IPSS-r. In three out of four patients, no mutations or MDS-associated immunophenotypic features were detected. One patients was diagnosed as MDS-MLD and three patients as MDS-RS-SLD according to the WHO 2016 classification. The ten most relevant cellular features that discriminated between MDS and non-MDS patients in the reference data were confirmed in the current validation cohort. All ten features of MDS patients in the validation cohort were significantly different from non-MDS patients of the reference cohort (all features, p < 0.00001) (Figure 2). Seven out of ten features were similar in MDS patients of the validation cohort compared to those of the MDS patients of the reference cohort (p>0.05) (Figure 2). Conclusion In this validation study, we confirmed accuracy of machine learning-based flow cytometry diagnostics in lower risk MDS. The workflow obtained 92% sensitivity, which is in accordance with results from our previous study (85-97%), and outperformed currently used diagnostic flow cytometry scores for MDS (i.e. Ogata score and iFS). In our previous study specificity was 95% in both reference and test cohorts. Cellular features, most discriminative for diagnosis, were confirmed in the validation cohort, emphasizing robustness of the method. Additional benefits of this approach are the reduction in analysis time to less than thirty seconds per patient, reduction of required antibodies and increased reproducibility. Disclosures van de Loosdrecht: celgene: Honoraria; novartis: Honoraria.

Lamotrigine add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review previously published in 2016. Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs. Lamotrigine, in combination with other antiepileptic drugs (add-on), can reduce seizures, but with some adverse effects. To determine the effects of lamotrigine on (1) seizures, (2) adverse-effect profile, and (3) cognition and quality of life, compared to placebo, when used as an add-on treatment for people with drug-resistant focal epilepsy. For the latest update of the review, we searched the following databases on 9 March 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to March 06, 2020). CRS Web includes randomized or quasi-randomized, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. No language restrictions were imposed. Randomised placebo-controlled trials of people with drug-resistant focal epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded, placebo-controlled. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant focal epilepsy. For this update, two review authors independently assessed the trials for inclusion, and extracted data. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), adverse effects, effects on cognition and quality of life. Primary analyses were by intention-to-treat. Sensitivity best- and worse-case analyses were undertaken to account for missing outcome data. Pooled risk ratios (RRs) with 95% confidence intervals (95% Cls) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, we calculated pooled RRs and 99% Cls. We did not identify any new studies for this update, therefore, the results and conclusions are unchanged. In previous updates of this review, the authors found five parallel add-on studies, eight cross-over studies in adults or children with drug-resistant focal epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks; treatment phases from eight to 36 weeks. Overall, 11 studies (1243 participants) were rated as having low risk of bias, and three (697 participants) had unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in four studies (563 participants). The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 trials, 1322 participants (adults and children); moderate-certainty evidence) indicating that lamotrigine was significantly more effective than placebo in reducing seizure frequency. The overall RR for treatment withdrawal (for any reason) was 1.11 (95% CI 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia (double vision), and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 trials; 1525 participants; high-certainty evidence); dizziness 2.00 (99% Cl 1.52 to 2.64;13 trials; 1768 participants; moderate-certainty evidence); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 trials, 944 participants; high-certainty evidence); nausea 1.81 (99% Cl 1.22 to 2.68; 12 studies,1486 participants; moderate-certainty evidence). The limited data available precluded any conclusions about effects on cognition and quality of life. No important heterogeneity between studies was found for any of the outcomes. Overall, we assessed the evidence as high to moderate certainty, due to incomplete data for some outcomes. Lamotrigine as an add-on treatment for drug-resistant focal seizures appears to be effective in reducing seizure frequency, and seems to be fairly well-tolerated. However, the trials were of relatively short duration and provided no evidence for the long term. Further trials are needed to assess the long-term effects of lamotrigine, and to compare lamotrigine with other add-on drugs.

Losigamone add-on therapy for focal epilepsy.

Epilepsy is a common neurologic disorder, affecting approximately 50 million people worldwide; nearly a third of these people have epilepsy that is not well controlled by a single antiepileptic drug (AED) and they usually require treatment with a combination of two or more AEDs. In recent years, many newer AEDs have been investigated as add-on therapy for focal epilepsy; losigamone is one of these drugs and is the focus of this systematic review. This is an update of a Cochrane Review first published in 2012 and updated in 2018. To investigate the efficacy and tolerability of losigamone when used as an add-on therapy for focal epilepsy. For the latest update on 20 August 2019, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE. CRS Web includes randomized or quasi-randomized, controlled studies from the Specialized Registers of Cochrane Review Groups including Cochrane Epilepsy, CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we searched trials registers and contacted themanufacturer of losigamone and authors of included studies for additional information. We did not impose any language restrictions. Randomized controlled, add-on studies comparing losigamone with placebo for focal epilepsy. Two review authors independently assessed study quality and extracted data. The primary outcomes were 50% or greater reduction in seizure frequency and seizure freedom; the secondary outcomes were treatment withdrawal and adverse events. Results are presented as risk ratios (RRs) with 95% confidence intervals (CIs) or 99% CIs (for the individual listed adverse events to make an allowance for multiple testing). Two studies involving a total of 467 participants, aged over 18 years, were eligible for inclusion. Both studies assessed losigamone 1200 mg/day or 1500 mg/day as an add-on therapy for focal epilepsy. We assessed one study as being of good methodological quality while the other was of uncertain quality. For the efficacy outcomes, results showed that participants taking losigamone were significantly more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.76, 95% CI 1.14 to 2.72; 2 studies, 467 participants; moderate-quality evidence), but associated with a significant increase of treatment withdrawal when compared with those taking placebo (RR 2.16, 95% CI 1.28 to 3.67; 2 studies, 467 participants; moderate-quality evidence). For the tolerability outcomes, results indicated that the proportion of participants who experienced adverse events in the losigamone group was higher than in the placebo group (RR 1.34, 95% CI 1.00 to 1.80; 2 studies, 467 participants; moderate-quality evidence). Dizziness was the only adverse event significantly reported in relation to losigamone (RR 3.82, 99% CI 1.69 to 8.64; 2 studies; 467 participants; moderate-quality evidence). Neither study reported the proportion of participants achieving seizure freedom. A subgroup analysis according to different doses of losigamone showed that a higher dose of losigamone (1500 mg/day) was associated with a greater reduction in seizure frequency than lower doses, but was also associated with more dropouts due to adverse events. The results of this review showed that losigamone did reduce seizure frequency but was associated with more treatment withdrawals when used as an add-on therapy for people with focal epilepsy. However, the included studies were of short-term duration and uncertain quality. Future well-designed randomized, double-blind, placebo-controlled studies with a longer-term duration are needed. We did not find any new studies since the last version of this review. We judged the overall quality of the evidence for the outcomes assessed as moderate.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Placebo Effect in Obsessive-Compulsive Disorder (OCD). Placebo Response and Placebo Responders in OCD: The Trend Over Time.

BackgroundPlacebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during 1989-1999. Placebo response is generally considered as the extent to which placebo treatment is associated with core symptom improvement. In this analysis, we used Joinpoint regression to assess the time trend of both placebo response and placebo responder rates according to the year of publication with no time restriction in OCD drug trials.MethodWe included drug and/or psychotherapy trials vs. placebo from PubMed, Embase, CINAHL, and PsycINFO retrieved through the search (placebo OR sham) AND (obsessive* OR OCD). We included studies through investigator consensus. We then performed on data of included studies log-linear joinpoint segmented regression models using a p<0.05 cutoff.ResultsWe included 113 studies from 112 published papers. Placebo mean annual response rates in OCD studies significantly increased from 1991 to 2017 with an annual percent change (APC) of 0.66%, while placebo mean annual responder rates also significantly increased from 2010 to 2017, with an APC of 5.45%. Drug mean annual response rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72%, while the corresponding responder rates did not show statistically significant APC changes between 1984 and 2017.ConclusionWe observed a tendency for placebo to increase both measures of response in OCD clinical drug trials through the years that tend to approximate the responses shown by drugs. Changes in the type of study (moving from classical head to head comparisons to add-on studies in treatment-resistant populations) and countries involved in experimentation may partially account for some portion of these results. It appears that placebo effects are becoming more elusive and out of control.

Herbal medicine (Hyeolbuchukeo-tang or Xuefu Zhuyu decoction) for treating primary dysmenorrhea: A systematic review and meta-analysis of randomized controlled trials.

Primary dysmenorrhea is a condition characterized by painful menstrual cramps that usually occurs in the absence of any identifiable pathological condition among menstruating women, with the prevalence estimates varying between 45% and 95%. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered as a standard treatment for primary dysmenorrhea; however, the failure rate of NSAIDs is often 20% to 25% and these drugs commonly cause adverse effects. In this review, we investigated the current evidence related to the effectiveness of Xuefu Zhuyu decoction (XZD) or Hyeolbuchukeo-tang, a traditional herbal formula, as a treatment for primary dysmenorrhea. Literature search was conducted about randomized controlled trials (RCTs) for XZD on primary dysmenorrhea. PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure Database, Oriental Medicine Advanced Searching Integrated System, and other Chinese, Korean, Japanese databases were searched up to December 20, 2017. Two independent reviewers extracted and assessed the data. The main outcome domains were visual analogue scale (VAS) score and response rate. Among 475 publications, 8 RCTs involving 1048 patients were finally included. Methodological quality of included RCTs was relatively low. In 4 add-on design studies, XZD plus western medication (WM) group showed better response rate as compared to the WM sole therapy (relative risk 1.18, 95% confidence interval [1.11, 1.25], P < .01). VAS score after the 3rd month of treatment in the XZD plus WM group was also lower than that in the WM group (mean difference -0.45, 95% confidence interval [-0.79, -0.12], P < .01). In 4 XZD versus WM design studies, XZD sole therapy showed better response rate than did WM sole therapy (relative risk 1.26, 95% confidence interval [1.06, 1.49], P < .01). The existing trials showed a favorable effect of XZD for the management of primary dysmenorrhea. However, the efficacy of XZD on primary dysmenorrhea is not conclusive owing to the small number of studies and the high risk of bias. Large-scale, long-term RCTs with rigorous methodological input are needed to clarify the role of XZD for the management of primary dysmenorrhea. CRD42016050447 in PROSPERO 2016.

Vagus Nerve Stimulation for Depression: A Systematic Review.

Background: Depression is a common mental disorder worldwide. Psychological treatments and antidepressant medication are the usual treatments for depression. However, a large proportion of patients with depression do not respond to the treatments. In 2005, Vagus nerve stimulation was approved for the adjunctive long-term treatment of chronic or recurrent depression in adult patients experiencing a major depressive episode who had failed to respond to four or more adequate antidepressant treatments. However, the efficacy of VNS for treating depression remains unclear. Accordingly, we performed a systematic review to evaluate the efficacy and safety of VNS.Methods: We conducted a systematic review in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Systematic search was performed in the database of Pubmed, Embase, CENTRAL, and Web of science for identifying the suitable trials. Suicidal rate was considered as the primary outcome in this review.Result: Only two randomized sham controlled add-on studies including 255 cases (134 with VNS treatment and 121 control cases) were included in this review. None of the studies reported suicidal rate. We performed a qualitative analysis and it is suggested that there was no significant statistic difference between VNS and sham VNS on the score of 24-item Hamilton Rating Scale for Depression (HAMD24) (MD: −2.40, 95% CI: −7.90 to 3.10). Similar findings were also reported on improvement percentage of HAMD24 (MD: 1.00, 95%CI: −6.06 to 8.06), Montgomery-Asberg Depression Rating Scale (MADRS) (MD: 4.70, 95%CI: −2.98 to 12.38) and 30 item Inventory of Depressive Symptomalogy-Self-Report (IDS-SR30) (MD: 4.9, 95%CI: −1.89 to 11.69). However, a marginal difference of Beck Depression Inventory self-rating score was detected between the real and sham treatment (MD: 7.80, 95% CI: 0.34 to 15.26). Aminor effect of IDS-SR30was also found in real VNS group (RR: 2.33, 95% CI: 1.07 to 5.10).Conclusion: The efficacy and safety of VNS for depression is still unclear. Further randomized controlled trials are needed to confirm the efficacy and safety of VNS.

Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation.

To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

Effectiveness of long-term treatment with SGLT2 inhibitors: real-world evidence from a specialized diabetes center

BackgroundDiabetes is a progressive disease needing multiple drugs for achieving and maintaining good glycemic control. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) is a novel class of anti-diabetic agent which offers several beneficial effects. However, the long-term effectiveness in clinical practice and safety data of SGLT2 inhibitors is limited, especially in Asian patients. To better understand the effectiveness of SGLT2i in clinical practice, we conducted a retrospective evaluation of patients with diabetes on SGLT2i.MethodsThis retrospective observational study uses data of patients with diabetes who had been prescribed SGLT2i and continued to use at least 6 months at Theptarin Hospital, Bangkok. The characteristics of patients, changes in glycemic control and body weight at 3, 6, 12, 18, 24 months and the last follow-up were evaluated.ResultsA total of 189 patients with diabetes (females 50.3%, mean age 59.9 ± 12.3 years, T2DM 97.3%, duration of diabetes 16.3 ± 9.2 years, baseline BMI 29.9 ± 6.1 kg/m2, baseline HbA1c 8.8 ± 1.6%) were prescribed SGLT2i during the study period. At the time of first SGLT2i prescription, 80.4% used three or more other anti-diabetic agents concomitantly and 34.6% used insulin concomitantly. 151 patients who continue to use at least 6 months were included in analysis. At the last follow-up (median time 16 months), overall median HbA1c reduction and weight reduction were 1.0% and 1.5 kg, respectively. While glycemic control could maintain up to 18 months, weight loss gradually rebounded after the first 6 months and then backed to baseline body weight at 18 months (78.2 ± 18.0 kg vs. 78.0 ± 17.8, p value = 0.324). The incidence of adverse drug reactions of special interest (polyuria, volume depletion-related events, urinary tract infection, genital infection, and hypoglycemia) was 2.1, 1.6, 2.1, 2.6, and 7.9%, respectively.DiscussionThis real-world study confirmed long-term durability of glycemic control with SGLT2i in not only monotherapy, but also add-on studies with other oral anti-diabetic drugs and/or insulin treatment. However, weight loss became evident early after 6 weeks then reached slightly rebounds after 24 weeks until the end of follow-up. Further studies should be done towards a better understanding of treatment with SGLT2i in routine clinical practice.

Efficacy and safety of perampanel in Parkinson's disease. A systematic review with meta-analysis.

L-Dopa represents the mainstay of therapy of Parkinson's disease (PD), but its effectiveness is reduced with continued treatment and disease progression. Accordingly, there remains a need to explore novel treatment strategies to manage the signs and symptoms of the later disease stages. The aim of the study was to evaluate the efficacy and safety of adjunctive perampanel (PER) in patients with PD through a meta-analysis of existing trials. Randomized, placebo-controlled, double- or single-blind, add-on studies of PER in patients with PD were identified through a systematic literature search. The following outcomes were assessed: changes from baseline to final efficacy visit in total daily OFF time, activities of daily living during OFF time and motor function during ON time, incidence of adverse events (AEs), and treatment withdrawal. Four trials were included involving 2266 participants, 1449 and 817 for PER and placebo treatment groups, respectively. Four PER daily doses were tested, namely 0.5, 1, 2 and 4mg. There were no significant differences in any efficacy outcome between PER and placebo treated patients. The risk ratios (RRs) for AEs, severe AEs and treatment withdrawal were similar between placebo and PER at 0.5, 1 and 2mg; the 4mg daily dose was associated with an increased risk of AEs [RR 1.118 (1.047-1.193)], and withdrawal for AEs [RR 1.345 (1.034-1.749)] and for any reason [RR 1.197 (1.020-1.406)]. In PD patients experiencing motor fluctuations, adjunctive PER did not improve the motor state and was well-tolerated at the lower doses.

Felbamate as an add-on therapy for refractory partial epilepsy

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.