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Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10−8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Background Blonanserin transdermal patch therapy is now available in Japan for the treatment of schizophrenia and may provide several advantages over the tablet formulation. Objective The aim was to evaluate the long-term safety and efficacy of blonanserin transdermal patches in Japanese patients with schizophrenia. Methods An open-label study was conducted in adults with schizophrenia at 37 sites in Japan. Patients were enrolled in either cohort 1 or 2. Patients in cohort 1 received 8–16 mg/day blonanserin tablets for 6 weeks and then 40–80 mg/day blonanserin patches for 52 weeks. The dose of blonanserin patches was determined according to the dose of the tablets. In cohort 2, every patient started from 40 mg/day and then 40–80 mg/day blonanserin transdermal patches for 52 weeks. Both cohorts had 1–2 weeks of follow-up. Safety endpoints included the incidence of adverse events (AEs), treatment-related AEs, extrapyramidal AEs [also assessed using the change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score], the use of any concomitant antiparkinsonian drugs, and skin-related AEs, including skin irritation. Patients also underwent assessment of laboratory values including for serum prolactin concentration, vital signs, body weight, electrocardiographic (ECG) changes, and the corrected QT (QTc) interval. Suicidal ideation was assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS) score. Efficacy was assessed via duration of blonanserin transdermal patch treatment, Positive and Negative Syndrome Scale (PANSS) total and subscale scores, and Clinical Global Impression-Severity (CGI-S) scores. Other endpoints included total Drug Attitude Inventory 10 (DAI-10) scores, EuroQol-5 Dimension (EQ-5D) effect values, and a patient questionnaire about the dosage form. Results A total of 223 patients with consents, 117 in cohort 1 and 106 in cohort 2 were included in the study. Of the 117 patients in cohort 1, 108 were treated with blonanserin tablets, and 97 received blonanserin patches and were included in the safety analysis set. In cohort 2, 103 of the 106 patients were treated with blonanserin transdermal patches and were included in the safety analysis set. In total, 91 patients were male (45.5%). The mean age was 43.8 years. Discontinuation occurred in 40 patients (41.2%) in cohort 1 and 44 patients (42.7%) in cohort 2. Discontinuation resulted from AEs in 18.6% (cohort 1) and 11.7% (cohort 2) and from withdrawal of consent in 13.4% (cohort 1) and 20.4% (cohort 2), and seven patients overall discontinued due to skin reactions. AEs were reported in 174 patients (87.0%), and 13 serious AEs occurred in 12 patients (6.0%), of which six patients were in cohort 1 and six patients were in cohort 2. Serious AEs were six schizophrenia (n = 6) and seven other AEs (n = 6), which included impulse-control disorder, fracture, epistaxis, asthma, pneumonia aspiration, pneumonia hemophilus, and pneumonia. The most common AEs were nasopharyngitis (n = 62, 31.0%), application site erythema (n = 45, 22.5%), application site pruritus (n = 23, 11.5%), and akathisia (n = 20, 10.0%). AE incidence was similar in cohort 1 (84.5%) and cohort 2 (89.3%). Extrapyramidal and skin-related AEs were reported in 51 patients (25.5%) and 83 patients (41.5%), respectively. None of these AEs were serious. The mean change from baseline in total DIEPSS score at Week 52 {last observation carried forward [LOCF] (standard deviation [SD])} was −0.1 (1.55), indicating no marked effect. In terms of concomitant medications used in cohort 1 and cohort 2, 33.0% (32/97) and 22.3% (23/103) used antiparkinsonian drugs, respectively. The majority of skin-related AEs occurred early in treatment and were appropriately managed with topical therapies. Of the patients who answered “No” to all C-SSRS categories at baseline (n = 129), 13 patients (10.1%) were evaluated as having emergence of suicidal ideation. Among patients who answered “No” to all C-SSRS suicidal behavior categories at baseline (n = 172), one (0.6%) was evaluated as having suicidal behavior during blonanserin transdermal patch treatment. There were no clinically significant changes in laboratory tests or examinations, including prolactin level, vital signs, body weight, ECG, metabolism-related parameters, and QTc interval. The mean (SD) change in body weight was − 0.04 (4.561) kg and − 0.67 (6.841) kg in cohort 1 and cohort 2, respectively. The mean changes from baseline in PANSS total score at Week 52 (LOCF [SD]) were − 0.1 [11.6] and − 3.4 [15.3] in cohort 1 and 2, respectively. PANSS scores did not change after switching from tablet to patch formulation in cohort 1 and decreased over the 52 weeks of treatment with the blonanserin patches. The mean change from baseline in CGI-S score at Week 52 (LOCF [SD]) was − 0.2 [1.03] in both cohorts combined. After 52 weeks of blonanserin patch treatment, the total DAI-10 score increased or remained unchanged compared with baseline in 82 of the 129 patients (63.6%) for whom these data were available. In the intention-to-treat population of the combined cohorts (n = 200), the mean (SD) change from baseline in EQ-5D score at the last assessment was − 0.0365 (0.17603). Patients’ attitudes to the blonanserin transdermal patches were generally positive. Conclusions Blonanserin transdermal patches are safe and effective in the long-term treatment of schizophrenia. ClinicalTrials.gov registration NCT02335658. Electronic supplementary material The online version of this article (10.1007/s40263-019-00692-6) contains supplementary material, which is available to authorized users.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

For prevention and early detection of dependence on hypnotics such as benzodiazepines (BZDs) or its agonists, a withdrawal symptom scale specialized for this kind of drug has long been sought. In this study, the benzodiazepine hypnotics withdrawal symptom scale (BHWSS) was developed using item response theory (IRT). This study enrolled 121 chronic insomnia patients (mean age 46.1 ± 15.6 years) who had been treated with hypnotics for 3 or more months. The patients were asked to fill a questionnaire that was developed by selecting questions from Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) and Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) on the basis of the symptoms triggered by reduction or abrupt cessation of the intake of hypnotics. A factor analysis was performed to verify the assumption that the new scale had one dimension. We drew item response category characteristic curves, following the IRT. Besides statistical considerations, clinical implications were also incorporated to select the 12 items used to construct the BHWSS questionnaire. Using the analyses based on IRT, 6 items each were selected from BWSQ and CIWA-B. The cumulative proportion of contribution of the first factor, obtained by factor analysis, was found to be 0.36. Cronbach’s α coefficient and McDonald’s ω coefficient were calculated to be 0.86 and 0.87, respectively. The total score of 12 items increased monotonically with the increasing level of withdrawal symptoms. The BHWSS could potentially become a practical tool for estimating the degree of BZD withdrawal symptoms.

The prevalence of restless legs syndrome and its impact on daytime function were explored in a hemodialysis population, particularly addressing the response consistency of restless legs syndrome symptoms. A two-point internet-based questionnaire survey with a one week interval was administered to 645 subjects of a hemodialysis population. Five hundred and four candidates (332 men and 172 women with mean [SD] age of 59.1 [12.8] years) with hemodialysis who completed the two surveys were selected for analysis. Questionnaire items included personal data, four criteria items for diagnosis of restless legs syndrome, Athens Insomnia Scale, Center for Epidemiologic Studies Depression Scale, Short Form 8-items for health survey, and items of the International Restless Legs Syndrome Severity Scale. Factors associated with deteriorated mental component summary and physical component summary on Short Form 8-items for health survey and depression were assessed. Prevalence of restless legs syndrome was the rate of those meeting the four diagnostic criteria items for this disorder in both surveys: 12.9%. Restless legs syndrome category defined by response consistency to the restless legs syndrome criteria items was significantly associated with the physical component summary score deterioration. This two-point survey indicated reliable prevalence of restless legs syndrome in a hemodialysis population, and revealed that stability of restless legs syndrome symptoms might contribute to the presence of certain daytime dysfunctions in this population.

Background We previously presented a group theoretical model that describes psychiatric patient states or clinical data in a graded vector-like format based on modulo groups. Meanwhile, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, the current version), is frequently used for diagnosis in daily psychiatric treatments and biological research. The diagnostic criteria of DSM-5 contain simple binominal items relating to the presence or absence of specific symptoms. In spite of its simple form, the practical structure of the DSM-5 system is not sufficiently systemized for data to be treated in a more rationally sophisticated way. To view the disease states in terms of symmetry in the manner of abstract algebra is considered important for the future systematization of clinical medicine. Results We provide a simple idea for the practical treatment of the psychiatric diagnosis/score of DSM-5 using depressive symptoms in line with our previously proposed method. An expression is given employing modulo-2 and −7 arithmetic (in particular, additive group theory) for Criterion A of a ‘major depressive episode’ that must be met for the diagnosis of ‘major depressive disorder’ in DSM-5. For this purpose, the novel concept of an imaginary value 0 that can be recognized as an explicit 0 or implicit 0 was introduced to compose the model. The zeros allow the incorporation or deletion of an item between any other symptoms if they are ordered appropriately. Optionally, a vector-like expression can be used to rate/select only specific items when modifying the criterion/scale. Simple examples are illustrated concretely. Conclusions Further development of the proposed method for the criteria/scale of a disease is expected to raise the level of formalism of clinical medicine to that of other fields of natural science.

Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10−7, odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10−8, OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA (P=5.8×10−7). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.

During the course of our studies to sequence mitochondrial DNA (mtDNA) in patients with bipolar disorder and in healthy control subjects,1, 2 we found a 3-bp deletion, m.8348–8350, in a lymphoblastoid cell line (LCL) of a healthy Japanese man (49-years old). This deletion occurred in the region of mitochondrial tRNALys (Figure 1a). The deletion was not, however, detected in the lymphocyte DNA obtained from this subject (Figure 1a). Allele-specific polymerase chain reaction, which can detect a 0.1% mutation of total mtDNA, did not reveal the 3-bp deletion in the lymphocytes (Figure 1b). This finding suggests that the acquisition of this deletion occurred during formation of the LCL, although the possibility of a bottleneck effect cannot be ruled out.

Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variation (CNV) between twins, we performed CNV analysis and found the copy number profiles were nearly identical between the twin pairs except for immunoglobulin-related regions. Among the three genes we obtained as candidate regions showing distinct difference of DNA methylation between one of the two pairs, hypermethylation of SLC6A4, encoding HTT, in the bipolar twin was only confirmed by bisulfite sequencing. Then, promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case-control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of HTTLPR, and mRNA expression level was lower in BD patients carrying the S/S genotype. Finally, DNA methylation of the same site was also higher in the postmortem brains of BD patients. This is the first study to report the role of epigenetic modification of SLC6A4 in BD using an unbiased approach, which provides an insight for its pathophysiology.