Yuji Hashizume

Melatonin therapy for REM sleep behavior disorder

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia with clinical symptoms that include punching, kicking, yelling and leaping out of bed in sleep. Polysomnographic (PSG) finding showed REM sleep without muscle atonia. Clonazepam is generally used for treating RBD symptoms but melatonin was reported to be effective so we reconfirmed the effect of melatonin on RBD patients in the present study. We used melatonin (3–9 mg/day) which could ameliorate problem sleep behaviors remarkably, as well as %tonic activity in PSG variables. In the present study, melatonin was reconfirmed to be effective in RBD symptoms, especially for patients with low melatonin secretion, while its mechanism was not clearly known in the present study.

Questionnaire relating to sleep paralysis

A sleep survey was conducted on 8162 citizens. The cumulative experience rate of sleep paralysis was 39.6%. The initial occurrence of sleep paralysis peaked at age 16 years. In addition to being higher in young people than in older subjects, the incidence of sleep paralysis was also higher among women than among men, and was significantly higher among shift worker than non‐shift worker, and among persons engaged in the nursing profession than those not engaged in the nursing profession. The experience rate of sleep paralysis demonstrated a strong correlation with the frequency of dreaming, the experience rate of nightmares, times and regularity of going to bed and waking up, and particularly with the degree of insomnia.

Effects of acetazolamide on the sleep apnea syndrome and its therapeutic mechanism

Abstract Twenty male patients with sleep apnea syndrome were treated with acetazolamide (AZM), a carbonic anhydrase inhibitor. In 14 of the patient a significant decrease was found in the number of apnea, apnea index and % apnea time (percentage of time spent with apnea to the total sleep time) with improvement in sleep structure, clinical symptoms, such as insomnia, daytime excessive sleepiness and snoring. A significant decrease was also observed in arterial blood pH and HCO−3 in the 14 improved patients. On the other hand, no improvement occurred in the parameters of sleep apnea and sleep with AZM in the remaining six patients. Moreover, metabolic acidosis and an improvement in arterial blood gases did not occur with AZM in the six patients.

Effect of zolpidem on sleep architecture and its next-morning residual effect in insomniac patients: a randomized crossover comparative study with brotizolam.

This study was conducted to determine the effect of zolpidem (ZOL) 10 mg orally on the sleep architecture and the next-morning residual effect in patients with non-organic insomnia (ICD-10) as compared to the effect of brotizolam (BTM) 0.25 mg orally, a widely used short-acting benzodiazepine (BZD) hypnotic in Japan, in a randomized, crossover comparative study. Fourteen patients with non-organic insomnia (3 males and 11 females; mean age of 54.9+/-S.D. 8.9 years). First three nights with placebo, middle three nights with either ZOL 10 mg or BTM 0.25 mg, and last three nights again with placebo in each session (a total of two sessions). Primary endpoints were polysomnography findings of sleep stages, sleep parameters, and sleep latency (SL) in the morning to examine calculable sleepiness as a residual effect. Secondary endpoint was sleep quality assessed by self-assessment questionnaire. At 150 min after Tmax, both ZOL and BTM significantly increased stage 2 (S2), and ZOL showed significantly longer slow wave sleep (SWS; stage 3+4) as compared to BTM. Stage wake was significantly increased by ZOL at the first withdrawal night and by BTM at the second withdrawal night. ZOL did not affect SL after rising, whereas BTM showed significantly shorter SL. Both drugs reduced the number of nocturnal awakenings and improved subjective sleep quality. The common adverse drug reaction (ADR) was sleepiness (3 patients) in each treatment. All events were mild. No serious adverse events occurred. ZOL is as effective as BTM in improving subjective sleep quality in patients with psychophysiological insomnia (PPI). ZOL has advantages over BTM in having a unique profile of increasing SWS with less next-morning residual effect.

New susceptibility variants to narcolepsy identified in HLA class II region

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

A polymorphism in CCR1/CCR3 is associated with narcolepsy.

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.

Fluctuations of rectal and tympanic temperatures with changes of ambient temperature during night sleep

Abstract Many studies have demonstrated a decline in core temperature during slow wave sleep (SWS) in animals and humans. However, there are few studies that have investigated core temperature fluctuation during rapid eye movement sleep (REM) at different ambient temperatures. This study examined the effects on core temperature of continuous hot or cold exposure during sleep. Ten male subjects were exposed to hot and cold stress from 00 h to 1:00 h, when SWS is most predominant, and from 5:00 h to 7:00 h, when REM is predominant. Rectal temperature (Tr) and tympanic temperature (Tt) were monitored for 3 days, and polysomnographies (PSG) were recorded from 23:00 h to 7:00 h. The experiments lasted 3 weeks for each subject, over 2 consecutive nights each week (including an adaptation night and an experimental night). On the experimental night, subjects were exposed to hot (29°C) or cold (21°C) ambience. The core temperature fluctuation under the hot or cold ambience were compared with under the thermoneutral ambience. Under hot ambience, Tr declined significantly in the first 2 hours of sleep, but Tt did not change. In the last 2 hours, both Tr and Tt were significantly elevated. Under cold ambience, both Tr and Tt declined significantly in the first 2 hours. However, in the last 2 hours, neither Tr nor Tt showed any change. The result that Tr and Tt rose in hot ambience during the last 2 hours when REM is predominant suggests that body temperature during REM is influenced by ambient temperature.

An association analysis of HLA-DQB1 with narcolepsy without cataplexy and idiopathic hypersomnia with/without long sleep time in a Japanese population

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.

Study on withdrawal of hypnotics: questionnaire on hypnotic use and its withdrawal.

To investigate the situation and problems contingent to hypnotic use and withdrawal, we conducted a questionnaire of outpatients. Only 41% of the patients were satisfied with their sleep and 53% of the patients took hypnotics. As regards the period, 83% of users had used them for more than 1 year and 19% had used them for more than 10 years. Although 90% of patients perceived efficacy of hypnotics, 67% felt more or less anxious about hypnotic use. Sixty‐seven per cent of patients had actually withdrawn from the drugs or decreased dosage before. More than half the patients’ conditions worsened after the withdrawal or reducing dosage.

Situation and problem of administration methods and the intermission of hypnotics

Abstract The results of a questionnaire survey suggested four problems that might prolong the administration of benzodiazepine hypnotics without suspending the medication. First, psychiatrists did not actively consider the necessity of suspension of medication with hypnotics. Second, the period between improvement of insomnia and initiation of dose reduction was long, whereas the period between initiation of dose reduction and discontinuation was short. Third, to suspend medication of a hypnotic, every‐other‐day administration was used for the very short‐acting and short‐acting types, and substitution of the intermediate‐acting or long‐action type for the drugs with a short half‐life were performed frequently. Finally, dose reduction and intermission of medication induced rebound insomnia, withdrawal symptoms, and recurrence of insomnia.