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Background Although antidepressant monotherapy is recommended for patients with major depressive disorder (MDD), they often do not respond to it, necessitating alternatives such as electroconvulsive therapy (ECT). However, maintenance pharmacotherapy after ECT has remained unestablished. This study, conducted at 240 facilities throughout Japan, aimed to explore maintenance pharmacotherapy after ECT for 3,749 inpatients with MDD. Methods The patients were divided into two groups, one that underwent ECT (ECT group, N  = 521) and another that did not (non-ECT group, N  = 3,273), for the comparison of clinical characteristics and prescription details at discharge. The primary outcome of this study was the prescription rate of antidepressant monotherapy at discharge, while the secondary outcomes included prescription rates of specific combination regimens, such as antidepressant plus lithium. Results We identified 198 prescription patterns involving antidepressants in the ECT group. Analysis by drug category revealed distinctive patterns: there was no statistically significant difference in prescription rates for antidepressant monotherapy between the ECT and non-ECT groups ( N  = 118, 22.6% vs. N  = 932, 28.4%). In contrast, the prescription rate for the combination of antidepressant and antipsychotic medications was significantly higher in the ECT group ( N  = 188, 36.0% vs. N  = 941, 28.7%). The combination of antidepressant and mood stabilizer was also more frequent in the ECT group ( N  = 35, 6.7% vs. N  = 130, 3.9%), although this difference did not reach statistical significance after Bonferroni correction. At the drug level, additional distinctive patterns emerged: among antidepressant monotherapies, nortriptyline use was significantly more common in the ECT group ( N  = 9, 1.7% vs. N  = 11, 0.3%). For mood stabilizers, restricting the analysis to lithium revealed a markedly higher rate in the ECT group ( N  = 30, 5.7% vs. N  = 35, 1.0%). Conclusions These findings highlight the complexity of treatment decisions managing of MDD after ECT and emphasize the need for structured prospective research on the effectiveness of specific maintenance pharmacotherapies after ECT.

Abstract Study Objectives To assess long-term efficacy and safety of lemborexant (LEM), a novel dual orexin receptor antagonist, versus placebo in adults with insomnia disorder. Methods This was a 12-month, global, multicenter, randomized, double-blind, parallel-group phase 3 study comprising a 6-month placebo-controlled period (reported here) followed by a 6-month active-treatment-only period (reported separately). A total of 949 participants with insomnia (age ≥18 years) were randomized, received treatment with an oral dose of placebo or LEM (5 mg [LEM5] or 10 mg [LEM10]) and were analyzed. Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Results Decreases from baseline in patient-reported (subjective) sleep onset latency and subjective wake after sleep onset, and increases from baseline in subjective sleep efficiency, were significantly greater with LEM5 and LEM10 versus placebo. Significant benefits over placebo were observed at the end of month 6, and at most time points assessed over the 6-month period, indicating long-term sustained efficacy of LEM. A significantly greater percentage of sleep onset responders and sleep maintenance responders were observed with LEM treatment versus placebo. Participants treated with LEM reported a significant improvement in quality of sleep after 6 months versus placebo. The majority of TEAEs were mild or moderate. There was a low rate of serious TEAEs and no deaths. Conclusions LEM5 and LEM10 provided significant benefit on sleep onset and sleep maintenance in individuals with insomnia disorder versus placebo, and was well tolerated. Clinical trial registration ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39

Background and Objective Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. In two phase III, 12-week studies in patients with insomnia disorder, daridorexant improved sleep and daytime functioning while maintaining a favorable safety profile. The objective of this 40-week extension study was to assess the long-term safety and tolerability of daridorexant. Methods Adults with insomnia disorder who completed the 12-week studies were invited to enroll in this double-blind extension study. Patients originally randomised to daridorexant (10 mg/25 mg/50 mg) remained on their respective treatments; patients randomised to placebo were re-randomised to daridorexant 25 mg or placebo. The 40-week treatment period was followed by a 7-day placebo run-out. The primary objective was to assess safety/tolerability. Exploratory objectives were to evaluate the efficacy of daridorexant on sleep (self-reported total sleep time) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire). Results In total, 804 patients were enrolled in the study, of whom 801 received at least one dose of the study treatment and 550 patients (68.4%) completed the study. Overall incidence of treatment-emergent adverse events was similar across groups (35–40%). Daridorexant did not induce next-morning sleepiness and no withdrawal-related symptoms or rebound were observed after treatment discontinuation. Improvements in sleep and daytime functioning were maintained through to the end of the study and were most pronounced with daridorexant 50 mg. Daridorexant 50 mg, compared with placebo, increased self-reported total sleep time by a least-squares mean of 20.4 (95% confidence interval [CI] 4.2, 36.5), 15.8 (95% CI − 0.8, 32.5) and 17.8 (95% CI − 0.4, 35.9) minutes and decreased (i.e., improved) Insomnia Daytime Symptoms and Impacts Questionnaire total scores by a least-squares mean of − 9.3 (95% CI − 15.1, − 3.6), − 9.5 (95% CI − 15.4, − 3.5) and − 9.1 (95% CI − 15.6, − 2.7), at weeks 12, 24 and 36 of the extension study, respectively. Conclusions Treatment with daridorexant, for up to 12 months, was generally safe and well tolerated. Exploratory efficacy analyses suggest that the sustained improvements in sleep and daytime functioning with daridorexant 50 mg support its use for long-term treatment of insomnia disorder, without concerns of new safety signals. Clinical Trial Registration ClinicalTrials.gov (NCT03679884) [first posted: 21 September, 2018], https://clinicaltrials.gov/ct2/show/NCT03679884 . Plain Language Summary Insomnia disorder is the long-term inability to fall asleep or stay asleep with a significant impact on daily life. Left inadequately treated, this disorder may increase the risk of other health problems. For patients with insomnia disorder who require a sleep medication, many drugs are not recommended for long-term use and there is an unmet need for one that can be used safely and effectively over the long term. Daridorexant is a new insomnia treatment that was approved for adults following positive results in two 12-week clinical studies. Both studies showed that, in patients with insomnia disorder, daridorexant improved night-time sleep and patients’ ability to function during the day, while avoiding major safety concerns. Patients who completed these two studies could continue into a 40-week extension study enabling the safety and tolerability of daridorexant to be investigated for up to 1 year. Treatment remained double blind for the entire 1-year period. The extension study showed that daridorexant, at all doses studied (10 mg, 25 mg, 50 mg), continued to be generally safe and well tolerated. Patients showed no signs of tolerance, physical dependence, rebound nor any excessive daytime sleepiness. Exploratory efficacy analyses suggest that improved night-time and daytime symptoms of insomnia were sustained, in particular with the highest approved dose, 50 mg, and there were no signs that the benefits of the drug were wearing off at the end of the 1 year. These results support the use of daridorexant 50 mg for the long-term treatment of insomnia disorder in adults.

Remimazolam (Byfavo™) is a benzodiazepine sedative that is indicated for the induction and maintenance of procedural sedation in adults. Remimazolam was efficacious in three phase III trials in patients requiring endoscopies. Significantly higher procedure success rates (composite of the completion of the procedure, top-up doses of study drug within predefined limits and no requirement for rescue therapy) were observed with remimazolam than with placebo, with the majority of placebo recipients requiring rescue midazolam. Furthermore, remimazolam significantly reduced times to onset of sedation and recovery in comparison with placebo (plus rescue). Remimazolam is generally well tolerated, with hypotension and hypertension the most common adverse drug reactions. Higher doses of concomitant fentanyl with remimazolam may increase the incidence of adverse drug reactions and deep sedation events. However, no correlation was observed between depth of sedation and vital signs. In summary, remimazolam is a useful option for the induction and maintenance of procedural sedation. Although pharmacoeconomic analyses for remimazolam are not yet available, the rapid induction of sedation and short recovery times with remimazolam may be beneficial in improving patient throughput in clinics. Plain Language Summary Procedural sedation may be administered to patients to improve their comfort during diagnostic or therapeutic procedures. Remimazolam (Byfavo™) is a rapidly metabolised, intravenously administered benzodiazepine sedative, which induces sedation by binding to specific neurotransmitter receptors in the brain. It is approved for the induction and maintenance of procedural sedation in adults. Remimazolam had superior efficacy to placebo in three clinical trials in patients requiring an endoscopy. Most (> 80%) remimazolam recipients successfully completed their endoscopy (≥ 97% of patients) within a predefined dosage regimen of remimazolam (≥ 84%), without requiring midazolam as a rescue sedative (≥ 90%). Conversely, the vast majority (≥ 90%) of placebo recipients required rescue sedation. Times until the onset of sedation and until the patient was ready for discharge post procedure were significantly shorter with remimazolam than with placebo plus rescue. Remimazolam is generally well tolerated, with hypotension and hypertension being the most common adverse drug reactions. Overall, remimazolam is a fast-acting option for procedural sedation and is associated with short recovery times, which has the potential to improve patient throughput in clinics.

Infectious disease epidemics have become more frequent and more complex during the 21st century, posing a health threat to the general public and leading to psychological symptoms. The current study was designed to investigate the prevalence of and risk factors associated with depression, anxiety and insomnia symptoms during epidemic outbreaks, including COVID-19. We systematically searched the PubMed, Embase, Web of Science, OVID, Medline, Cochrane databases, bioRxiv and medRxiv to identify studies that reported the prevalence of depression, anxiety or insomnia during infectious disease epidemics, up to August 14th, 2020. Prevalence of mental symptoms among different populations including the general public, health workers, university students, older adults, infected patients, survivors of infection, and pregnant women across all types of epidemics was pooled. In addition, prevalence of mental symptoms during COVID-19 was estimated by time using meta-regression analysis. A total of 17,506 papers were initially retrieved, and a final of 283 studies met the inclusion criteria, representing a total of 948,882 individuals. The pooled prevalence of depression ranged from 23.1%, 95% confidential intervals (95% CI: [13.9–32.2]) in survivors to 43.3% (95% CI: [27.1–59.6]) in university students, the pooled prevalence of anxiety ranged from 25.0% (95% CI: [12.0–38.0]) in older adults to 43.3% (95% CI: [23.3–63.3]) in pregnant women, and insomnia symptoms ranged from 29.7% (95% CI: [24.4–34.9]) in the general public to 58.4% (95% CI: [28.1–88.6]) in university students. Prevalence of moderate-to-severe mental symptoms was lower but had substantial variation across different populations. The prevalence of mental problems increased over time during the COVID-19 pandemic among the general public, health workers and university students, and decreased among infected patients. Factors associated with increased prevalence for all three mental health symptoms included female sex, and having physical disorders, psychiatric disorders, COVID infection, colleagues or family members infected, experience of frontline work, close contact with infected patients, high exposure risk, quarantine experience and high concern about epidemics. Frequent exercise and good social support were associated with lower risk for these three mental symptoms. In conclusion, mental symptoms are common during epidemics with substantial variation across populations. The population-specific psychological crisis management are needed to decrease the burden of psychological problem and improve the mental wellbeing during epidemic.

Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy. In the multinational, phase 3 NOVA trial in adult patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly prolonged median progression-free survival, irrespective of the presence or absence of a germline BRCA ( gBRCA ) mutation and irrespective of the presence or absence of homologous recombinant deficiency. Niraparib is also in development for use in other solid tumours, including breast and prostate cancer. This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Background Brivaracetam (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. Objective We 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). Methods We 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). Results Sixteen 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. Conclusions Cenobamate 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.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the pathogenesis of asthma. Tezepelumab (tezepelumab-ekko; TEZSPIRE™) is a first-in-class human IgG2λ monoclonal antibody that inhibits the action of TSLP. Administered subcutaneously, it is being developed by Amgen and AstraZeneca for the treatment of asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic spontaneous urticaria and eosinophilic oesophagitis. Tezepelumab received its first approval on 17 December 2021 as an add-on maintenance treatment for patients aged ≥ 12 years with severe asthma in the USA; it is the only biologic approved for severe asthma with no phenotype (e.g. eosinophilic or allergic) or biomarker limitations. A regulatory assessment of tezepelumab for the treatment of asthma is currently underway in the EU and Japan. Tezepelumab received orphan drug designation for the treatment of eosinophilic oesophagitis in October 2021 in the USA, and is undergoing clinical development for the treatment of COPD, CRSwNP and chronic spontaneous urticaria. This article summarizes the milestones in the development of tezepelumab leading to this first approval for the add-on maintenance treatment of patients aged ≥ 12 years with severe asthma.

Insomnia is a highly prevalent condition associated with significant morbidity, reduction in quality of life, and increase in healthcare costs, and is a risk factor for multiple physical and mental disorders. The primary treatment modality is cognitive behavioral therapy for insomnia (CBT-I) but this is associated with difficulties with access and higher cost as well as poor response in some patients. Therefore, pharmacotherapy for insomnia is common and hypnotic agents are among the most frequently prescribed medications in the United States. Older medications for insomnia are limited by their side effect burden and narrow therapeutic window. Newer hypnotics, on the other hand, have been shown to have a better safety profile and longer term efficacy. While some studies have shown that long-term hypnotic use is associated with adverse outcomes, the current evidence is equivocal. The decision to treat chronic insomnia disorder with long-term hypnotics should be individualized and balance the potential risks of continuing hypnotic medication use with the risks of untreated persistent insomnia and associated functional limitations. This clinical review discusses the currently available medication options to treat insomnia, their mechanisms of action, dosing, and side effect profiles. This review also provides guidance on long-term management of hypnotics and the use of these medications in the elderly, those with medical comorbidities, and other special populations.

Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered dual orexin type 1 and type 2 (OX 1 and OX 2 ) receptor antagonist (DORA) being developed for the treatment of insomnia. It was selected from a pool of drug candidates on the basis of an expected effect duration of ≈ 8 h at a dose of 25 mg, with a half-life intended to minimize residual effects that might impair daytime functioning. Based on the results of two pivotal phase III trials, daridorexant was recently approved in the USA for the treatment of adult patients with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. This article summarizes the milestones in the development of daridorexant leading to this first approval.