Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial.

BACKGROUND: Antihistamines with strong sedative-hypnotic properties are frequently prescribed for insomnia secondary to allergy, but the potential risks of such administration have not been fully elucidated. SUBJECTS AND METHODS: This randomized, double-blind, placebo-controlled crossover study was conducted to evaluate next-day sleepiness and psychomotor performance following the administration of antihistamines. Twenty-two healthy male participants participated in four drug administration sessions with more than a 1-week interval between the sessions. Either zolpidem 10 mg, or diphenhydramine 50 mg, or ketotifen 1 mg, or a placebo was administered before sleep, and polysomnography was conducted to evaluate sleep. In the morning and afternoon of the day after administration, the participants were evaluated for subjective sleepiness, objective sleepiness, and psychomotor performance. RESULTS: The antihistamines with high blood-brain barrier-crossing efficiency were significantly associated with sleepiness and psychomotor performance decline the next day. Ketotifen showed the strongest carryover effect, followed by diphenhydramine. Compared with the placebo, no significant carryover effect was observed with zolpidem. CONCLUSION: The results suggest that the risk-benefit balance should be considered in the ready use of antihistamines that easily cross the blood-brain barrier for alleviating secondary insomnia associated with allergies.

Time estimation during sleep relates to the amount of slow wave sleep in humans.

Humans have the ability to estimate the amount of time that has elapsed during sleep (time estimation ability; TEA) that enables a subset of individuals to wake up at a predetermined time without referring to a watch or alarm clock. Although previous studies have indicated sleep structure as a key factor that might influence TEA during sleep, which sleep parameters could affect the TEA has not been clarified. We carried out an experimental study in which 20 healthy volunteers participated in six time estimation trials during the 9-h nighttime sleep (NS) experiment or daytime sleep (DS) experiment. The time estimation ratio (TER, ratio of the subjective estimated time interval to actual time interval) decreased significantly from the first to the sixth trial in both the NS and DS experiments. TER correlated positively with slow wave sleep (SWS) in both experiments, suggesting that SWS was a determining factor in accurate time estimation, irrespective of circadian phase they slept. No other sleep parameters showed steady influence on TEA. The present findings demonstrate that longer period of SWS is associated with the longer sleep time they subjectively experienced during sleep.

Inhibited autonomy for promoting physical health: qualitative analysis of narratives from persons living with severe mental illness.

BACKGROUND: Autonomy is a key factor in the reduction of inequitable physical healthcare among people with severe mental illness compared with the general population.AimsTo clarify the critical mechanism underlying autonomy in physical health promotion based on the perspectives of people with severe mental illness. METHOD: We employed a conventional content analysis of narrative data from the Healthy Active Lives in Japan (HeAL Japan) workshop meetings. RESULTS: 'Inhibited autonomy' was extracted as a central component and shaped by the users' experiences, both in a healthcare setting and in real life. This component emerged based on the lack of an empowerment mechanism in psychiatric services. CONCLUSIONS: A barrier to the encouragement of autonomy in physical health promotion was found in current psychiatric services. An effective strategy should be explored to foster an empowerment mechanism in psychiatric and mental health services.Declaration of interestNone.

Clinical significance and correlates of behaviorally induced insufficient sleep syndrome.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the demographic variables and clinical characteristics of behaviorally induced insufficient sleep syndrome (BIISS) and to compare it with the other major hypersomnia disorders. PATIENTS AND METHODS: One-thousand two-hundred forty-three consecutive patients referred to the outpatient clinic for complaint of excessive daytime sleepiness (EDS) were retrospectively investigated. RESULTS: The rate of BIISS in patients with EDS was 7.1%, predominant in males. The mean age of initial visit was younger than that for obstructive sleep apnea syndrome (OSAS), while the mean age of onset of symptoms was older than that for idiopathic hypersomnia, narcolepsy, and circadian rhythm sleep disorders. The mean Epworth sleepiness scale (ESS) score before treatment was lower than that for narcolepsy but higher than that for both OSAS and circadian rhythm sleep disorders. Twenty-two percent of BIISS cases reported having accidents or near-miss accidents during the five-year period preceding the investigation, and this group showed higher ESS scores than the group without accidents. CONCLUSIONS: Our findings showed that an unignorably large number of people suffer from BIISS, and that people with severe cases of the disorder are at high risk for getting into an accident. Characteristics and demographic information could be helpful for making a differential diagnosis of BIISS.

Adequacy of continuation and maintenance treatments for major depression in Japan.

Guidelines for treating depression often recommend continuing antidepressants at least for 6 months after remission. Whether this recommendation is implemented in daily practices represents a serious concern. We aimed to examine adequacy of continuation and maintenance treatment in Japan. A naturalistic prospective follow-up study with mood disorders was undertaken in 23 psychiatric departments from all over Japan. A total of 95 patients diagnosed with major depression were followed up every month until treatment termination and every 6 months thereafter. In this study, the cohort received 45.1 (SD = 64.7) mg of imipramine or equivalent per day during continuation phase, and about 74% were prescribed inadequate doses, i.e. less than 75 mg/day. At maintenance phase immediately before relapse, average dosage was 42.0 (SD = 74.7) mg/day and 83% were prescribed inadequate doses. There is gross under-treatment of depression during continuation and maintenance phases in Japan.

Reduced frontal asymmetry of delta waves during all-night sleep in schizophrenia.

Delta wave deficits during sleep have been observed in patients with schizophrenia. Decreased slow-wave sleep is reported to be associated with negative symptoms. Frontal lobe dysfunction is also believed to underlie negative symptoms of schizophrenia. This study was designed to identify functional abnormalities in schizophrenia manifested on patients' electroencephalograms. Polysomnograph examinations were performed in 12 healthy male volunteers and 11 male outpatients with schizophrenia. We investigated the laterality of frontal cortical delta waves in patients with schizophrenia and in healthy control subjects. Laterality of frontal cortex delta wave counts during all-night sleep was investigated by computer analysis. Total delta wave counts were lower in patients with schizophrenia than in control subjects. Control subjects showed significantly higher delta wave counts in the right frontal cortex than in the left. This asymmetry was not observed in patients with schizophrenia. These findings suggest that reduced right frontal delta wave dominance is involved in the pathophysiology of schizophrenia.

Clinical analyses of sighted patients with non-24-hour sleep-wake syndrome: a study of 57 consecutively diagnosed cases.

STUDY OBJECTIVES: The objective of this study was to clarify the clinical features of sighted patients with non-24-hour sleep-wake syndrome. DESIGN: Clinical analyses of consecutive patients suffering from non-24-hour sleep-wake syndrome. SETTING: The sleep disorders clinic at Kohnodai Hospital, National Center of Neurology and Psychiatry, Japan. PATIENTS: Fifty-seven patients who were diagnosed consecutively as having non-24-hour sleep-wake syndrome between 1991 and 2001 were included in the study. MEASUREMENTS AND RESULTS: The clinical features and sleep characteristics of the patients were analyzed. A semistructured psychiatric interview that included the criteria for Axis I or II disorders of Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised was conducted, and relationships between psychiatric problems and non-24-hour sleep-wake syndrome were analyzed. The patient cohort included 41 (72%) men and 16 (28%) women. The onset of non-24-hour sleep-wake syndrome had occurred during the teenage years in 63% of the cohort, and the mean ( +/-SD) period of the sleep-wake cycle was 24.9 +/- 0.4 hours (range 24.4-26.5 hours). The mean sleep length of the patients was 9.3 +/- 1.3 hours, and 44% of them had a sleep length of between 9 and 10 hours. Psychiatric disorders had preceded the onset of non-24-hour sleep-wake syndrome in 16 patients (28%); of the remaining 41 patients, 14 (34%) developed major depression after the onset of non-24-hour sleep-wake syndrome. CONCLUSIONS: These results represent the first detailed clinical review of a relatively large number of sighted patients with non-24-hour sleep-wake syndrome.

Cerebral white matter blood flow is constant during human non-rapid eye movement sleep: a positron emission tomographic study.

This study aimed to identify brain regions with the least decreased cerebral blood flow (CBF) and their relationship to physiological parameters during human non-rapid eye movement (NREM) sleep. Using [(15)O]H(2)O positron emission tomography, CBF was measured for nine normal young adults during nighttime. As NREM sleep progressed, mean arterial blood pressure and whole brain mean CBF decreased significantly; arterial partial pressure of CO(2) and, selectively, relative CBF of the cerebral white matter increased significantly. Absolute CBF remained constant in the cerebral white matter, registering 25.9 +/- 3.8 during wakefulness, 25.8 +/- 3.3 during light NREM sleep, and 26.9 +/- 3.0 (ml.100 g(-1).min(-1)) during deep NREM sleep (P = 0.592), and in the occipital cortex (P = 0.611). The regression slope of the absolute CBF significantly differed with respect to arterial partial pressure of CO(2) between the cerebral white matter (slope 0.054, R = - 0.04) and frontoparietal association cortex (slope - 0.776, R = - 0.31) (P = 0.005) or thalamus (slope - 1.933, R = - 0.47) (P = 0.004) and between the occipital cortex (slope 0.084, R = 0.06) and frontoparietal association cortex (P = 0.021) or thalamus (P < 0.001), and, with respect to mean arterial blood pressure, between the cerebral white matter (slope - 0.067, R = - 0.10) and thalamus (slope 0.637, R = 0.31) (P = 0.044). The cerebral white matter CBF keeps constant during NREM sleep as well as the occipital cortical CBF, and may be specifically regulated by both CO(2) vasoreactivity and pressure autoregulation.

Diurnal fluctuation of time perception under 30-h sustained wakefulness.

Previous studies have reported that time perception in humans fluctuates over a 24-h period. Behavioral changes seem to affect human time perception, so that the fluctuation in human time perception may be the result of such changes due to self-determined activities. Recently, we carried out a study in which a healthy human cohort was asked to perform simultaneously loaded cognitive tasks under controlled conditions, and found that time perception decreased linearly from morning to evening. In addition, the variations in time perception were not a consequence of behavioral changes. It remains to be elucidated whether diurnal variations in time perception are a consequence of circadian rhythm or of some homeostatic changes that are attributable to accumulated wake time. The effects of circadian rhythm on time perception were investigated in eight healthy young male volunteers by conducting 10-s time production tasks under 30-h constant-routine conditions. Core body temperature and serum melatonin and cortisol levels were measured during the course of the study. Produced time exhibited a diurnal variation and was strongly correlated with circadian variations in core body temperature and serum melatonin levels. These results suggest that human short-term time perception is under the influence of the circadian pacemaker.

Deactivation by benzodiazepine of the basal forebrain and amygdala in normal humans during sleep: a placebo-controlled [15O]H2O PET study.

OBJECTIVE: The authors' goal was to identify differences in regional brain activity between physiological and benzodiazepine-induced sleep to clarify the brain structures involved in the drug's hypnotic effect. METHOD: Using positron emission tomography, they compared regional cerebral blood flow during non-REM sleep in nine volunteers treated with placebo or triazolam, a short-acting benzodiazepine, in a double-blind, crossover design. RESULTS: Blood flow in the basal forebrain and amygdaloid complexes was lower during non-REM sleep when subjects were given triazolam than when they were given placebo. CONCLUSIONS: The hypnotic effect of the benzodiazepines may be mediated mainly by deactivation of the forebrain control system for wakefulness and also by the anxiolytic effect induced by deactivation of the emotional center.

A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders.

Recent studies have shown that functional variations in clock genes, which generate circadian rhythms through interactive positive/negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIepsilon), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIepsilon induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24), we analyzed all of the coding exons of the human CKIepsilon gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIepsilon. The N408 allele was less common in both DSPS (p = 0.028) and N-24 patients (p = 0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant (p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22-0.79). In vitro kinase assay revealed that CKIepsilon with the S408N variation was approximately 1.8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIepsilon plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.

Sleep and circadian rhythm disturbances in patients with delayed sleep phase syndrome.

STUDY OBJECTIVES: The objective of this study was to clarify sleep characteristics and pathophysiology in patients with delayed sleep phase syndrome (DSPS), which is a major circadian rhythm sleep disorder subtype. DESIGN: Polysomnography was performed for 2 consecutive nights and core body temperature was sampled for 7 consecutive days, including the polysomnography study period, in all subjects. Findings were compared and statistically analyzed between patients with DSPS and matched controls. SETTING: Sleep disorders unit in National Center Hospital. PARTICIPANTS: 11 DSPS patients and 11 age-matched healthy volunteers. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep latency, total sleep time, wakefulness after sleep-onset, and the amount and percentage of Stage 1 sleep were greater in DSPS patients than in volunteers. Sleep efficiency and the amount and percentage of slow wave sleep were lower in DSPS patients than in volunteers. Compared with the healthy volunteers, DSPS patients showed a decreased number and different temporal distribution of high-voltage and low-frequency delta waves. The time of minimum body temperature appeared earlier in the sleep phase for the patients than for the volunteers. Significant correlation was found between the amount of slow wave sleep and the time from sleep onset to minimum body temperature and between the amount and percentage of slow wave sleep and time from minimum body temperature to sleep offset. CONCLUSIONS: Disturbances were found in the sleep structure of patients with DSPS, and these disturbances were related to the discrepancy between patients and controls in the phase relationship difference between sleep and core body temperature rhythms.

Larger phase angle between sleep propensity and melatonin rhythms in sighted humans with non-24-hour sleep-wake syndrome.

STUDY OBJECTIVES: This study was aimed to clarify phase angle between sleep propensity and the circadian pacemaker in patients with non-24-hour sleep-wake syndrome (Non-24). DESIGN AND SETTING: A case-control study was underaken. PARTICIPANTS: Sighted patient with Non-24 (4 males and 1 female, aged 16 to 39 y), and sex- and age-matched healthy controls (12 males and 3 females, aged 19 to 35 y) participated the study. MEASUREMENT AND INTERVENTION: Following an actigraphic assessment of the sleep-wake cycle in their homes, the participants entered an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation. RESULTS: The period of the sleep-wake cycle observed at home was longer in the Non-24 patients (25.12 hours) than in the controls (24.02 hours, p<0.0001). The interval from sleep propensity (SP) onset to the melatonin midpoint (MLmid) was significantly shorter in the Non-24 patients than in the controls. The interval from the MLmid to the SP offset was significantly longer in the Non-24 patients than in the controls. CONCLUSIONS: It was postulated that Non-24 sufferers' delayed SP onset relative to the circadian pacemaker may accelerate the light-induced phase-delay, leading to sleep-wake cycle that is longer than 24 hours.

Circadian fluctuation of time perception in healthy human subjects.

Previous studies suggested that various psychophysiological factors have influences on human time perception. In particular, working memory loads, time of day, body temperature, and mood were known as important modifiers of time perception. The purpose of this study is to elucidate factors affecting the short-term time perception under controlled condition. Fourteen healthy young male adults participated in this study. Time perception sessions (TPS) were conducted 4 times at 0900, 1300, 1700 and 2100 h. The TPS consisted of five 10-s time production trials under five different conditions (control trial, those with reward, and 3 different dual-load working memory tasks). Subjective status was assessed using visual analogue scales (VAS). To verify a participant's vigilance state, an alpha attenuation coefficient (AAC) was calculated. Two-way repeated measures ANOVA for produced time revealed a significant main effect of session, but no effect of task or interaction. Although produced time was not correlated with AACs or VAS scores, there was a significant negative correlation between produced time and core body temperature. These results suggest that human short-term time perception may be more influenced by circadian rhythm than working memory load or psychophysiological status.

Time estimation during nocturnal sleep in human subjects.

It has been postulated that time estimation during nocturnal sleep in humans can be explained by an interval timing clock inside the brain. However, no systematic investigations have been carried out with respect to how the human brain perceives the passage of time during sleep. The brain mechanisms of over- or underestimation of time spent in sleep have not yet been clarified. Here, we carried out an experimental study in which 11 healthy volunteers participated in time estimation trials scheduled six times during 9 h nocturnal sleep periods, under carefully controlled conditions. The time estimation ratio (TER: a ratio of subjective passage of time to actual time interval) decreased significantly from the first to the sixth trial. Individual TER was positively correlated with slow wave sleep prior to the trial, while it was negatively correlated with REM sleep. Our results indicate that the human brain has an ability to estimate the passage of time during nocturnal sleep without referring to time cues, and that the accuracy of this function fluctuates from overestimation in the early hours of sleep to underestimation in the last hours of sleep.

The psychological aspects of patients with delayed sleep phase syndrome (DSPS).

OBJECTIVE: The current study attempts to define the psychological features of patients with delayed sleep-phase syndrome (DSPS). METHOD: We administered the Yatabe-Guilford test (Y-G test), Minnesota Multiphasic Personality Inventory (MMPI), Picture-Frustration study (P-F study) and Rorschach test to two groups, one of patients with DSPS (case group) and the other of people without psychiatric symptoms or insomnia (control group). RESULTS: Overall, the results of the tests indicate that patients with DSPS showed emotional features such as nervousness, depression and lack of control of emotional expression. Specific personality traits included introspection, defensiveness, aspiration for intellectual attainment with compulsivity, overly abstract thinking, unawareness of impulsivity to immediate gratification, perseverance and reduced cognitive ability. In addition, the patients with DSPS showed psychopathological features similar to those of neurosis, hypochondriasis, depression, conversion hysteria and psychopathic deviate. CONCLUSIONS: There seems to exist a definite psychological profile for patients with DSPS. (1) an excessive defense mechanism that increases nervousness and develops neurosis; (2) a high level of intellectual aspiration with compulsivity that makes the patients feel self-defeated, powerless and disappointed; (3) a tendency to egocentric emotion, inhibition and perseverance. These characteristics may worsen social withdrawal, causing a loss of social cues in synchronizing their circadian rhythm. Thus, the phase shift becomes more difficult and a vicious circle is constituted.

Circadian rhythms in humans' delta sleep electroencephalogram.

Eight healthy young male volunteers entered a 20-40 min ultrashort sleep-wake schedule for 78 h in the time-isolation facility. Rectal temperature was continuously recorded. Sleep electroencephalograms (EEGs) obtained during 20 min nap trials were stored in the computer and later analyzed by fast Fourier transform. A two-way repeated-measures ANOVA (with day and time-of-day as the repeated measures) revealed significant circadian rhythms in the powers of sigma and delta sleep EEGs, and in rectal temperature. These results obtained under conditions in which behavioral confounding factors of retiring and rising were experimentally minimized suggest that the circadian pacemaker contributes to determining the hours of day when one can sleep deeply.

Mutation screening of the human Clock gene in circadian rhythm sleep disorders.

We tested whether the human Clock (hClock) gene, one of the essential components of the circadian oscillator, is implicated in the vulnerability to delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake syndrome (N-24). Screening in the entire coding region of the hClock gene with PCR amplification revealed three polymorphisms, of which two predicted the amino acid substitutions R533Q and H542R. The frequencies of the R533Q and H542R alleles in patients with DSPS or N-24 were very low and not significantly different from those in control subjects. A T3111C polymorphism in the 3'-untranslated region of hClock, which had been reportedly associated with morning or evening preference for activity, was also investigated; the results showed that the 3111C allele frequency decreased in DSPS. Polymorphisms in the coding region of the hClock gene are unlikely to play an important role in the development of DSPS or N-24. The possible contribution of the T3111C polymorphism to DSPS susceptibility should be studied further.

[Recent topics on ethical issues in psychiatry, mental care and welfare].

This lecture focuses on several ethical issues on psychiatry research and psychiatric practice. The most important issue in ethics is informed consent in both the national guidelines on ethics in genomic study and epidemiological studies determined by the Ministry of Health, Welfare and Labor, Ministry of Education, Culture, Sports, Science and Technology and Ministry of Economy, Trade and Industry. They recommend researchers to obtain consent from subjects making free voluntary decisions after they are fully provided with the necessary information and explanation. The guidelines on ethics in genomic study strongly recommend organizing an ethical committee committed by several extramural members from the fields of law, social or human sciences. On the other hand, the guidelines on ethics in epidemiological study provide how to obtain informed consent in detail according to how projects are carried out. Strict requirements of informed consent tend to inhibit medical research conduct, in particular a research on post-mortem brain, which is one of the important research areas for elucidation of pathogenesis and pathophysiology of mental disorders. Recently a new trend to organize a brain bank by donation of the patient who has given consent before death. This is a proper way to collect post-mortem brain overcoming the ethical problems and it is our hope that this trend will develop in our country. Disclosure of medical records to patients is one of the most recent and debated issues in psychiatric practices. In 1999, the Ministry of Health and Welfare started investigations on whether medical records should be disclosed to patients. The report of the committee strongly recommends accelerating the disclosure of medical records. Responding to this report, several medical organizations issued a guideline. Recently, we carried out a questionnaire survey on the disclosure rate of medical records in the psychiatric departments of both medical school hospitals and national mental hospitals, where special committees have been organized to determine the disclosure of the medical records when a patient demands it officially. Contrary to our expectation the rate of disclosure demands was very low in both medical schools and national mental hospitals. The average number was only less than one case in medical schools, and less than 0.5 cases in national mental hospitals. It was speculated that patient requests demanding the disclosure of the records are mostly managed by the doctor in charge without consulting the special committee. Looking back the process of debate on the disclosure of medical records, several important issues, such as notice of diagnosis, informed consent, management of records, standardization of medical records, financial support to establish management system of medical records and so on, remain to be further examined thoroughly.

Impact of frequency of nightmares comorbid with insomnia on depression in Japanese rural community residents: a cross-sectional study.

OBJECTIVE: Nightmares and insomnia are known to be associated with the development and aggravation of depression. Our community-based study was conducted to clarify the relation between the impacts of nightmares and insomnia on depression. METHODS: A cross-sectional questionnaire-based survey was administered to residents of a rural community in Japan. In all, 2822 participants responded to questions assessing personal characteristics, the Pittsburgh Sleep Quality Index (PSQI) for assessing insomnia, and a 12-item version of the Center for Epidemiological Studies Depression scale (CES-D) for evaluating depression. Nightmare frequency was assessed using an item for nightmares on the PSQI. RESULTS: Nightmares more frequently occurred in participants with insomnia than those without (P < .01). Multiple regression analysis revealed that the scores of both nightmares and insomnia were significantly associated with the increase in depression score (nightmares (ß = 0.09, P < .01); insomnia (ß = 0.39, P < .01)). Participants with coexisting nightmares and insomnia showed higher depression scores than participants with insomnia alone or those with nightmares who did not have insomnia (P < .01). CONCLUSIONS: Insomnia and nightmares independently and additively impact the aggravation of depression.