Assessing the Real-World, Long-Term Impact of Lemborexant on Sleep Quality in a Home-Based Clinical Study.

Purpose: Both subjective and objective evaluations are essential for the treatment of insomnia. Lemborexant has been shown to be effective in the long-term based solely on a subjective basis, and no long-term objective measures have been evaluated under natural sleep conditions. Small, lightweight sleep electroencephalogram (EEG) monitor was used, instead of polysomnography, to objectively evaluate sleep at home 4 and 12 weeks after lemborexant treatment. Patients and Methods: Adults and elderly subjects with insomnia disorder, per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were enrolled in this open-label, single-arm, single-center trial. Objective and subjective measures of sleep were prospectively assessed. Sleep disturbance, excessive sleepiness, and depressive symptoms were assessed using questionnaires. Results: A total of 45 subjects were screened, of which 33 were enrolled. Paired t-tests were conducted to evaluate changes in sleep variables and compared with the baseline; subjects showed significant improvements in objective sleep efficiency (SE) and subjective sleep parameters at weeks 4 and 12 following treatment with lemborexant. When baseline values were taken into account, a repeated-multivariate analysis of variance (MANOVA) revealed statistically significant changes in the objective measures. Sleep disturbance, excessive sleepiness, and depressive symptoms improved after three months of lemborexant treatment. Conclusion: Furthermore, lemborexant therapy improved nocturnal sleep, when measured objectively using sleep EEG monitoring at home, and improved daytime sleepiness and depressive symptoms in older adults with insomnia disorder.

Comparison of Polysomnography, Single-Channel Electroencephalogram, Fitbit, and Sleep Logs in Patients With Psychiatric Disorders: Cross-Sectional Study.

BACKGROUND: Sleep disturbances are core symptoms of psychiatric disorders. Although various sleep measures have been developed to assess sleep patterns and quality of sleep, the concordance of these measures in patients with psychiatric disorders remains relatively elusive. OBJECTIVE: This study aims to examine the degree of agreement among 3 sleep recording methods and the consistency between subjective and objective sleep measures, with a specific focus on recently developed devices in a population of individuals with psychiatric disorders. METHODS: We analyzed 62 participants for this cross-sectional study, all having data for polysomnography (PSG), Zmachine, Fitbit, and sleep logs. Participants completed questionnaires on their symptoms and estimated sleep duration the morning after the overnight sleep assessment. The interclass correlation coefficients (ICCs) were calculated to evaluate the consistency between sleep parameters obtained from each instrument. Additionally, Bland-Altman plots were used to visually show differences and limits of agreement for sleep parameters measured by PSG, Zmachine, Fitbit, and sleep logs. RESULTS: The findings indicated a moderate agreement between PSG and Zmachine data for total sleep time (ICC=0.46; P<.001), wake after sleep onset (ICC=0.39; P=.002), and sleep efficiency (ICC=0.40; P=.006). In contrast, Fitbit demonstrated notable disagreement with PSG (total sleep time: ICC=0.08; wake after sleep onset: ICC=0.18; sleep efficiency: ICC=0.10) and exhibited particularly large discrepancies from the sleep logs (total sleep time: ICC=-0.01; wake after sleep onset: ICC=0.05; sleep efficiency: ICC=-0.02). Furthermore, subjective and objective concordance among PSG, Zmachine, and sleep logs appeared to be influenced by the severity of the depressive symptoms and obstructive sleep apnea, while these associations were not observed between the Fitbit and other sleep instruments. CONCLUSIONS: Our study results suggest that Fitbit accuracy is reduced in the presence of comorbid clinical symptoms. Although user-friendly, Fitbit has limitations that should be considered when assessing sleep in patients with psychiatric disorders.

LPS and its relationship with subjective-objective discrepancies of sleep onset latency in patients with psychiatric disorders.

Subjective-objective discrepancies in sleep onset latency (SOL), which is often observed among psychiatric patients, is attributed partly to the definition of sleep onset. Recently, instead of SOL, latency to persistent sleep (LPS), which is defined as the duration from turning out the light to the first consecutive minutes of non-wakefulness, has been utilized in pharmacological studies. This study aimed to determine the non-awake time in LPS that is most consistent with subjective sleep onset among patients with psychiatric disorders. We calculated the length of non-awake time in 30-s segments from lights-out to 0.5-60 min. The root mean square error was then calculated to determine the most appropriate length. The analysis of 149 patients with psychiatric disorders showed that the optimal non-awake time in LPS was 12 min. On the other hands, when comorbid with moderate or severe obstructive sleep apnea (OSA), the optimal length was 19.5 min. This study indicates that 12 min should be the best fit for the LPS non-awake time in patients with psychiatric disorders. When there is comorbidity with OSA, however, a longer duration should be considered. Measuring LPS minimizes discrepancies in SOL and provides important clinical information.

A Study of Factors Causing Sleep State Misperception in Patients with Depression.

Purpose: Sleep state misperception, which is the discrepancy between subjective and objective sleep, is often observed in patients with depression. This phenomenon may delay the remission of depression. Previous studies have focused on the total sleep time (TST) misperception, with many of these studies using actigraphy. Thus, our study investigated depressed patients with the exploratory aim of clarifying factors associated with the sleep state misperception including the wake after sleep onset (WASO) misperception, with their objective sleep additionally evaluated by polysomnography (PSG). Patients and Methods: We conducted a cross-sectional study. Before undergoing overnight PSG monitoring, 40 patients with depression completed questionnaires that included the Beck Depression Inventory (BDI), Epworth sleepiness scale, Temperament and Character Inventory, and the Pittsburgh sleep quality index. Patients were also asked to estimate their subjective sleep duration after they woke up in the morning. Based on this data, we calculated the misperception using the following formula: subjective sleep duration minus objective sleep duration. We compared each factor between negative and positive misperception groups and the multiple regression analysis was performed for TST and WASO misperception, respectively. Results: Although sleep architectures, age, severity of depression and obstructive sleep apnea (OSA) exhibited differences in underestimating or overestimating the WASO, only sex differences were associated with underestimating or overestimating their total sleep time (TST). Moreover, BDI, the severity of OSA, sleep architectures (N1% and N2%), and benzodiazepine (BZD) use were significantly correlated with WASO misperception, whereas only OSA severity was significantly correlated with TST misperception. A subsequent multiple regression analysis demonstrated the BDI was independently correlated with the WASO misperception (ß=0.341, p=0.049). Conclusion: In clinical practice, interventions especially for OSA, and the reduction of depressive symptoms are an important method for improving patient sleep perception. Moreover, current results suggest that BZD prescriptions should be avoided as well.

Prevalence of obstructive sleep apnea as assessed by polysomnography in psychiatric patients with sleep-related problems.

PURPOSE: Patients with psychiatric disorders often complain of sleep disturbances and are frequently suspected of obstructive sleep apnea (OSA). However, data regarding sleep problems evaluated by attended polysomnography (PSG) remain limited in this population. We analyzed the results of attended PSG from psychiatric patients with sleep-related problems to determine the prevalence and features of sleep disorders among this population. METHODS: We retrospectively investigated the attended PSG results of patients with psychiatric disorders: major depressive disorder, bipolar disorder, neurodevelopmental disorder, schizophrenia, neurocognitive disorder, anxiety disorder, somatic symptom disorder. RESULTS: Of 264 patients, 158 men (60%), mean age was 47 ± 19.9 years. More than half of the patients with major depressive disorder (62%), bipolar disorder (70%), schizophrenia (58%), neurocognitive disorders (55%), and somatic symptom disorder (56%) had OSA. Among the psychiatric patients with OSA, 62% of these patients had moderate to severe OSA. The risk factors for OSA were snoring, male, age, and body mass index. The presence of OSA was not associated with the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale score, or benzodiazepine, antipsychotic, or antidepressant use. Other sleep disorders were insomnia (19%), central disorders of hypersomnia (8%), restless legs syndrome/periodic limb movement of sleep (8%), rapid eye movement sleep behavior disorder (7%), and central sleep apnea syndrome (3%). CONCLUSIONS: PSG revealed that moderate to severe OSA was common in psychiatric patients with or without snoring. Subjective symptoms and psychotropics did not predict OSA. Therefore, PSG is needed to reveal sleep conditions in patients with psychiatric disorders.

FLUID study: study protocol for an open-label, single-centre pilot study to investigate the efFect of Lemborexant on sleep management in Japanese sUbjects aged 50 years and older with Insomnia Disorder.

INTRODUCTION: Bidirectional associations have been reported between sleep disturbance and both cognitive impairment, including Alzheimer's disease and amyloid beta-peptide (Aß) accumulation. These relationships can be explained by the glymphatic system, which acts as a garbage drainage system in the brain. As interstitial fluid dynamics are suggested to increase during sleep, clearance of Aß can be influenced by sleep disturbance or deprivation. We hypothesised that using lemborexant, an orexin receptor antagonist, to improve sleep quality would also improve the function of the glymphatic system. We plan to examine the effect of lemborexant on sleep quality and the glymphatic system among patients with insomnia disorder. METHODS AND ANALYSIS: This pilot study is designed as an open-label, single-arm, single-centre trial. Thirty patients aged 50 years and over with insomnia will be recruited. The participants will take lemborexant (5 mg) at bedtime for 12 weeks and undergo a home-based sleep study at baseline and weeks 4 and 12, as well as MRI examinations to evaluate the glymphatic system at baseline and week 12. The primary outcome will be changes in objective sleep parameters as evaluated using a sleep monitoring system. The secondary outcomes will be changes in subjective sleep parameters. The relationships between changes in sleep parameters and the glymphatic system will be evaluated using diffusion tensor image analysis along the perivascular space, which is called the ALPS-index. Sleep parameters and the ALPS-index will be analysed using a paired t-test or Pearson's correlation coefficient. ETHICS AND DISSEMINATION: The study protocol was approved by Nagoya University Certified Review Board. The findings from this research will be published in peer-reviewed journals and be presented at local, national and international conferences. TRIAL REGISTRATION NUMBER: jRCTs041210024.

Whole-exome sequencing identified a homozygous FNBP4 mutation in a family with a condition similar to microphthalmia with limb anomalies.

Microphthalmia with limb anomalies (MLA), also known as Waardenburg anophthalmia syndrome or ophthalmoacromelic syndrome, is a rare autosomal recessive disorder. Recently, we and others successfully identified SMOC1 as the causative gene for MLA. However, there are several MLA families without SMOC1 abnormality, suggesting locus heterogeneity in MLA. We aimed to identify a pathogenic mutation in one Lebanese family having an MLA-like condition without SMOC1 mutation by whole-exome sequencing (WES) combined with homozygosity mapping. A c.683C>T (p.Thr228Met) in FNBP4 was found as a primary candidate, drawing the attention that FNBP4 and SMOC1 may potentially modulate BMP signaling.

Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.

By exome sequencing, we found de novo SMARCB1 mutations in two of five individuals with typical Coffin-Siris syndrome (CSS), a rare autosomal dominant anomaly syndrome. As SMARCB1 encodes a subunit of the SWItch/Sucrose NonFermenting (SWI/SNF) complex, we screened 15 other genes encoding subunits of this complex in 23 individuals with CSS. Twenty affected individuals (87%) each had a germline mutation in one of six SWI/SNF subunit genes, including SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A and ARID1B.

De novo 5q14.3 translocation 121.5-kb upstream of MEF2C in a patient with severe intellectual disability and early-onset epileptic encephalopathy.

Recent studies have shown that haploinsufficiency of MEF2C causes severe intellectual disability, epilepsy, hypotonia, and cerebral malformations. We report on a female patient with severe intellectual disability, early-onset epileptic encephalopathy, and hypoplastic corpus callosum, possessing a de novo balanced translocation, t(5;15)(q13.3;q26.1). The patient showed upward gazing and tonic seizure of lower extremities followed by generalized clonic seizures at 4 months of age. Electroencephalogram showed hypsarrhythmia when asleep. By using fluorescent in situ hybridization (FISH), southern hybridization and inverse PCR, the translocation breakpoints were determined at the nucleotide level. The 5q14.3 breakpoint was localized 121.5-kb upstream of MEF2C. The 15q26.2 breakpoint was mapped 119-kb downstream of LOC91948 non-coding RNA. We speculate that the translocation may disrupt the proper regulation of MEF2C expression in the developing brain, resulting in severe intellectual disability and early-onset epileptic encephalopathy.

SMOC1 is essential for ocular and limb development in humans and mice.

Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice.

STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.

PURPOSE: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. METHODS: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. RESULTS: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. DISCUSSION: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.

Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay.

A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of four individuals (group A) with early-onset West syndrome, severe hypomyelination, poor visual attention, and developmental delay. Although haploinsufficiency of STXBP1 was involved in early infantile epileptic encephalopathy in a previous different cohort study (group B), no mutations of STXBP1 were found in two of the remaining three subjects of group A (one was unavailable). We assumed that another gene within the deletion might contribute to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is essential for proper myelination in zebrafish, turned out to be deleted. In two subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 was further screened in six unrelated individuals with WS and hypomyelination, but no mutations were found. Recombinant mutant (mut) and wild-type (WT) alpha-II spectrin could assemble heterodimers with beta-II spectrin, but alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II (mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid cells from two subjects with in-frame mutations. Clustering of ankyrinG and voltage-gated sodium channels at axon initial segment (AIS) was disturbed in relation to the aggregates, together with an elevated action potential threshold. These findings suggest that pathological aggregation of alpha/beta spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations were involved in pathogenesis of infantile epilepsy.

De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.

Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.