Pharmacological and non-pharmacological interventions for adults with ADHD: Protocol for a systematic review and network meta-analysis

Introduction It is unclear how pharmacological and non-pharmacological interventions compare with each other in terms of efficacy and tolerability for core symptoms and additional problems in adults with attention-deficit/hyperactivity disorder (ADHD). We aim to conduct the first network meta-analysis (NMA) comparing pharmacological and non-pharmacological interventions (or their combinations) in adults with ADHD. Methods and analysis We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for NMAs. We will search a broad set of electronic databases/registries and contact drug companies and experts in the field to retrieve published and unpublished randomised controlled trials (RCTs) (parallel or cross-over) of medications (either licensed or unlicensed) and any non-pharmacological intervention in adults (≥18 years) with ADHD. Primary outcomes will be: (1) change in severity of ADHD core symptoms, and (2) acceptability (all-cause discontinuation). Secondary outcomes will include tolerability (drop-out due to side effects) and change in the severity of emotional dysregulation, executive dysfunctions and quality of life. The risk of bias in each individual RCT included in the NMA will be assessed using the Cochrane Risk of Bias tool-version 2. We will evaluate the transitivity assumption comparing the distribution of possible effect modifiers across treatment comparisons. We will perform Bayesian NMA for each outcome with random-effects model in OpenBUGS. Pooled estimates of NMA will be obtained using the Markov Chains Monte Carlo method. We will judge the credibility in the evidence derived from the NMA using the CINeMA tool (which includes assessment of publication bias). We will conduct a series of sensitivity analyses to assess the robustness of the findings. Ethics and dissemination As this is the protocol for an aggregate-data level NMA, ethical approval will not be required. Results will be disseminated at national/international conferences and in peer-reviewed journals. PROSPERO registration number CRD42021265576

Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

Background: Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABAA receptors, binding at a non-benzodiazepine site. Objective: We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. Methods: We systematically searched (May, week 4, 2020) 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. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. Results: Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67–2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93–7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85–2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08–4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02–1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. Conclusions: Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo

Atogepant for the Prevention of Episodic Migraine in Adults: A Systematic Review and Meta-Analysis of Efficacy and Safety

Introduction: The inhibition of the calcitonin gene-related peptide (CGRP) pathway has attracted interest in pharmacological research on migraine. Atogepant is a potent, selective, orally available antagonist of the CGRP receptor approved as a preventive treatment of episodic migraine. This systematic review with meta-analysis aims to evaluate the efficacy and safety of atogepant for the prevention of episodic migraine in adult patients. Methods: Randomized, placebo-controlled, single or double-blinded trials were identified through a systematic literature search (December week 4, 2021). Main outcomes included the changes from baseline in monthly migraine days and the incidence of adverse events (AEs) and treatment withdrawal due to AEs. Mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs) were estimated. Results: Two trials were included, overall enrolling 1550 patients. A total of 408 participants were randomized to placebo, 314 to atogepant 10 mg, 411 to atogepant 30 mg, and 417 to atogepant 60 mg once daily. The mean age of the patients was 41.0 years and 87.7% were women. The reduction in the mean number of migraine days from baseline across the 12-week treatment period was significantly greater among patients treated with atogepant at either the daily dose of 10 mg (MD − 1.16, 95% CI − 1.60 to − 0.73, p < 0.001), 30 mg (MD − 1.15, 95% CI − 1.54 to − 0.76, p < 0.001), or 60 mg (MD − 1.20, 95% CI − 2.18 to − 0.22, p = 0.016) than with placebo. There were no differences in the occurrence of AEs and drug withdrawal due to AEs between atogepant and placebo groups. Constipation was more commonly observed in patients treated with atogepant at 30 mg/day than placebo (RR 5.19, 95% CI 2.00–13.46; p = 0.001). Treatment with atogepant at the daily dose of 60 mg was associated with a higher risk of constipation (RR 4.92, 95% CI 1.89–12.79; p = 0.001) and nausea (RR 2.73, 95% CI 1.47–5.06; p = 0.001) than placebo. Conclusion: Atogepant is an efficacious and overall well-tolerated treatment for the prevention of episodic migraine in adults

Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis

Background: Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability. Objective: The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques. Methods: Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs). Results: Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases. Conclusions: Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo

Screening and treatment of hypertension in older adults: Less is more?

Screening and treatment of hypertension is a cornerstone of cardiovascular disease (CVD) prevention. Hypertension causes a large proportion of cases of stroke, coronary heart disease, heart failure, and associated disability and is highly prevalent especially among older adults. On the one hand, there is robust evidence that screening and treatment of hypertension prevents CVD and decreases mortality in the middle-aged population. On the other hand, among older adults, observational studies have shown either positive, negative, or no correlation between blood pressure (BP) and cardiovascular outcomes. Furthermore, there is a lack of high quality evidence for a favorable harm-benefit balance of antihypertensive treatment among older adults, especially among the oldest-old (i.e., above the age of 80 years), because very few trials have been conducted in this population. The optimal target BP may be higher among older treated hypertensive patients than among middle-aged. In addition, among frail or multimorbid older individuals, a relatively low BP may be associated with worse outcomes, and antihypertensive treatment may cause more harm than benefit. To guide hypertension screening and treatment recommendations among older patients, additional studies are needed to determine the most efficient screening strategies, to evaluate the effect of lowering BP on CVD risk and on mortality, to determine the optimal target BP, and to better understand the relationship between BP, frailty, multimorbidity, and health outcomes

Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles

Systematic review of management for treatment-resistant depression in adolescents

Background: Current guidelines for treatment-resistant depression in adolescents remain inadequate. This study aimed to systematically review the management of treatment-resistant depression in adolescent patients. Methods: We conducted an electronic database search of PUBMED, EMBASE, Cochrane, Web of Science and PsycINFO for studies with adolescent treatment-resistant depression published up to January 2014. Treatment-resistant depression was defined as failure to respond to at least one course of psychological or pharmacological treatment for depression with an adequate dosage, duration, and appropriate compliance during the current illness episode. The Cochrane risk-of-bias method was used to assess the quality of randomized controlled trials. A meta-analysis of all active treatments was conducted. Results: Eight studies with 411 depressed adolescents that fit predetermined criteria investigated pharmacological treatments and psychotherapies. Six were open-label studies, and two were randomized controlled trials. The overall response rate for all active treatments investigated was 46% (95% CI 33 to 59; N = 411) with a moderately high degree of heterogeneity (I2 = 76.1%, 95% CI = 47%-86%). When only the two randomized trials were included, the overall response rate of active treatment was 53% (95% CI = 38-67; N = 347). In these randomized trials, SSRI therapy plus CBT was significantly more effective than SSRI therapy alone, while amitriptyline was not more effective than placebo. Conclusions: Approximately half of the adolescents who presented with treatment-refractory depression responded to active treatment, which suggests that practitioners should remain persistent in managing these challenging cases. The combination of antidepressant medication and psychotherapy should be recommended for adolescents who present with treatment-resistant depression

Treatment with disease modifying drugs for people with a first clinical attack suggestive of multiple sclerosis

This is the protocol for a review and there is no abstract. The objectives are as follows: To estimate the benefit and safety of all DMDs that have been evaluated in all studies (randomised and non-randomised) for early treatment. We will employ novel, high-quality methods for systematic reviews and network meta-analysis in collaboration with the Cochrane Multiple Interventions Group. To evaluate the quality of the evidence provided by existing studies. We will consider the credibility of included studies and other characteristics of the evidence base as we characterise conclusions pertaining to high, low or very low quality of evidence. We will undertake this review in accordance with the methods described by the template protocol published online and will use this template as we prepare the review