Inpatient phase-advance therapy for delayed sleep-wake phase disorder: a retrospective study.

PURPOSE: The efficacy of inpatient phase-advance therapy among patients with delayed sleep-wake phase disorder (DSWPD) has not been adequately investigated because response rates are considered low. We aimed to examine the efficacy of such treatment in this patient population. PATIENTS AND METHODS: The present retrospective study included data from 66 patients with DSWPD who had been admitted to Akita University Hospital for inpatient phase-advance therapy between September 1, 2005, and April 30, 2018. DSWPD was diagnosed based on the International Classification of Sleep Disorders, 3rd edition, criteria using electronic medical records. We examined remission rates during inpatient therapy as well as relapse rates at the time of the first outpatient examination following discharge. Univariate analysis was performed to investigate predictive factors for postinpatient therapy relapse. RESULTS: The rate of DSWPD remission over the course of inpatient phase-advance therapy was 100% (95% CI: 95.6%-100%), with a median duration of 1 day (IQR: 1-2 days; range: 1-9 days) until remission. The rate of relapse following discharge was 45.8% (95% CI: 32.7%-59.2%). Univariate analysis indicated that the rate of relapse was significantly higher for minors (under 18) than adults (18 and over), for those whose age at onset was below 16 years than for those whose age at onset was 16 or above, and for those with relatively low motivation for their occupation (P=0.0339, P=0.0136, and P<0.001, respectively). CONCLUSION: The rate of DSWPD remission under inpatient phase-advance therapy was remarkably high (100%), while the rate of relapse after discharge was ~50%. Further studies are required to determine the long-term prognosis of inpatient therapy, risk factors for relapse, and the types of treatment most effective for preventing relapse.

Total sleep deprivation followed by sleep phase advance and bright light therapy in drug-resistant mood disorders.

BACKGROUND: Drug-resistant depression is a major therapeutic issue in psychiatry and the development of non-drug therapies that treat drug-resistant depression is required. Sleep deprivation (SD) is a non-drug treatment classified as a form of chronotherapy in addition to bright light therapy (BLT) and sleep phase advance (SPA). Combined chronotherapy is hypothesized to improve drug-resistant depression. In this study, we investigated the benefits of total sleep deprivation (TSD) followed by SPA and BLT in drug-resistant depression alongside ongoing antidepressant medication and observed the added effectiveness of the combined chronotherapy. METHODS: Thirteen drug-resistant inpatients affected by a major depressive episode were studied. They were treated by TSD followed by SPA (three days) and BLT (five days) with ongoing drug treatment. Effectiveness was rated using the Hamilton Rating Scale for Depression (HAM-D), the Zung Self-Rating Depression Scale (SDS), and the Visual Analogue Scale (VAS) over 3 weeks. RESULTS: Significant improvements of depressive symptoms were observed in both objective mood ratings (HAM-D) and subjective mood ratings (SDS and VAS). Eight out of 13 patients maintained this responsiveness (50% or greater changes in HAM-D) across the study period. Moreover, no patients dropped out of the combined chronotherapy procedure. LIMITATIONS: The study did not have a placebo group, and more subjects may be needed. CONCLUSION: The trial of combined chronotherapy successfully induced rapid improvement in depressive symptoms in drug-resistant patients without early relapse or obvious side effects.

[Chronotherapy can be a useful adjunctive therapy in treatment-resistant depression].

Although the treatment of depression is mainly based on antidepressant drugs, depressive patients are often resistant to drug treatments. Chronotherapy (sleep deprivation, bright light therapy, and sleep phase advance) is one of the non-drug treatments of depression, which ease depression by manipulation of sleep-wake schedule or biological rhythms. There are several advantages to using sleep deprivation for treatment of depression, including early response, a high efficacy rate (approximately 60%), few side effects, and efficacy for drug-resistant depression. On the other hand, relapse is common; there is substantial burden for patients and doctors; and no medical fee is obtained. Therefore, this treatment is not widely used in Japan. However, methods for increasing and sustaining the efficacy of sleep deprivation have been reported. It is possible to increase and sustain the efficacy of sleep deprivation in combination with medication (antidepressant drug, lithium, etc.), bright light therapy and/ or sleep phase advance. Because we sometimes encounter patients who are resistant to general drug treatment, adding sleep deprivation to the treatment choices may overcome drug-resistant depression and shorten treatment duration.

Individual traits and environmental factors influencing sleep timing: a study of 225 Japanese couples.

Behavioral and physiological processes, such as sleep-wakefulness, thermoregulation, and hormone secretion, exhibit 24-h rhythms in most organisms. These biological rhythms are driven by the circadian clock system and are entrained by the external environment, which in the case of humans includes social time schedules. Couples might be ideal experimental subjects to discriminate between individual traits and environmental factors, as they share lifestyle habits but not genetic backgrounds. In this study, sleep timing was compared between married Japanese couples (n = 225) who had lived together for 1 yr or more (mean 17 yrs). Additionally, the authors evaluated the influence of individual traits and environmental factors on an individual's sleep timing per each couple. The results reveal that the sleep timings of a couple are mainly associated with the chronotypes of the husband and wife, whereas the sleep timings are significantly influenced by certain environmental factors. The findings suggest that chronotype remains one of the major determinants of an individual's sleep onset and wake times. Understanding an individual's chronotype may help improve the quality of life issues surrounding sleep.

Expression profiles of PERIOD1, 2, and 3 in peripheral blood mononuclear cells from older subjects.

AIMS: Circadian clocks regulate daily rhythms of behavior and physiology such as the sleep-wake cycle and hormonal secretion. Numerous characteristics of the behavioral and physiological processes change with age. In this study, we evaluated the circadian clockwork in older people by measuring daily profiles of PERIOD (PER) gene expression in peripheral blood mononuclear cells (PBMCs). MAIN METHODS: Blood samples were collected from 6 healthy older subjects (mean age 62 years) at 2-h intervals over a 24-h period under a semi-constant routine condition where masking effects are minimized. PBMCs were isolated from whole blood and temporal mRNA expression profiles of PER1, PER2, and PER3 were determined by RT-PCR. Phases of the PER rhythms, and times of sleep onset and offset were determined using data from those subjects who showed significant 24-h rhythms. The values for the parameters were compared between the older subjects and 8 young control subjects (mean age 21 years). KEY FINDINGS: Prominent daily rhythms of PER1, PER2, and PER3 mRNA levels, advanced sleep-wake timing and advanced phases of PER rhythms were observed in the older subjects compared to the young controls. There was no significant age-related phase difference in PER1 or PER2 rhythm with respect to sleep timing; however, PER3 expression pattern was altered in the older subjects. SIGNIFICANCE: This preliminary study shows that human circadian clockwork in PBMCs remains intact at least until the presenile stage and suggests that the altered PER3 expression pattern may reflect decreased homeostatic sleep drive in older people.

Expression profiles of 10 circadian clock genes in human peripheral blood mononuclear cells.

The circadian clock system regulates daily rhythms of physiology and behavior. The mammalian master clock in the suprachiasmatic nuclei orchestrates these biological rhythms in peripheral tissues. Since blood is the most accessible tissue source, we sought to dissect the human circadian clock system by characterizing clock gene expression in human peripheral blood mononuclear cells (PBMCs) isolated from eight young, healthy subjects. By evaluating the temporal expression profiles of 10 circadian clock genes, we found that Period 1 (Per1), Per2, and Per3 are rhythmically expressed in human blood samples. Our results suggest that evaluating the rhythmic expression of human Per genes could reveal an individual's circadian phenotype.

Dissociation between objective psychomotor impairment and subjective sleepiness after diazepam administration in the aged people.

The aim of the present study was to clarify whether subjective sleepiness accurately reflects benzodiazepine-related decline in psychomotor function after taking benzodiazepines (BZPs) in aged people. Subjects were eight healthy, young (mean age, 19.8 years) and seven healthy, older (mean age, 60.9 years) men. Placebo and diazepam (DZP) were administered orally in a single-blind crossover manner to the young subjects (placebo, 5 mg DZP and 10 mg DZP) and to the older subjects (placebo and 5 mg DZP). Plasma drug concentration, choice reaction time (CRT) as an objective measure of psychomotor function, and the Stanford Sleepiness Scale (SSS) as a measure of subjective sleepiness were monitored every 20 min from 1000 until 1600 h, being the drug administered at 1200 h. Pharmacokinetic variables did not differ significantly between the two age groups. DZP at 10 mg in young subjects induced significant increases in both the CRT and SSS score. DZP at 5 mg induced no significant increase in SSS score in either age group but did induce a significant increase in CRT only in the older subjects that matched that in young subjects given 10 mg DZP. The older subjects suffered from dissociation between subjective sleepiness and objective psychomotor impairment under DZP treatment. Such individuals may underestimate the detrimental effects on brain function.

Enhanced heat loss and age-related hypersensitivity to diazepam.

Whether elderly people suffer from age-related changes in pharmacokinetics and/or pharmacodynamics with administration of benzodiazepines is still a matter of controversy. We investigated the course of brain function and thermoregulation after oral administration of a standard benzodiazepine, diazepam (DZP), in 8 healthy young men (mean age, 19.8 years; range, 18 to 23 years) and 8 healthy middle-aged and older men (mean age, 60.9 years; range, 53 to 71 years). Placebo or DZP was administered in a single-blind crossover manner to the young men (placebo, 5-mg, 10-mg DZP) and to the older men (placebo, 5-mg DZP), and plasma DZP concentration, choice reaction time, proximal body temperature, and distal body temperature were monitored with high time resolution under a modified constant routine condition to exclude masking effects. Whereas there was no evidence of age-related alterations in pharmacokinetics between the 2 groups, the older subjects, in comparison to the young subjects, showed a more delayed choice reaction time in response to the same plasma DZP level, suggesting that hypersensitivity is related to increased age. DZP at 5 mg in the older subjects induced acute and transient hypothermia to the same degree as that induced by DZP at 10 mg in the young subjects. The distal-proximal body temperature gradient (difference between distal body temperature and proximal body temperature), an indicator of blood flow in distal skin regions, showed strong positive correlation with the delay in choice reaction time in both groups. These findings suggest that hypersensitivity to benzodiazepine in older persons may be due, at least in part, to age-related changes in thermoregulation, especially in the heat loss process.

Similar profiles in human period1 gene expression in peripheral mononuclear and polymorphonuclear cells.

Increasing amounts of data have indicated the physiological significance of circadian clock gene regulation in various peripheral cells. In the present study, we examined expression of the human homolog of period1 (hPer1) in peripheral mononuclear cells (MNCs) and polymorphonuclear neutrophils (PMNs) in seven healthy young male volunteers (mean age, 21.0 years; range, 19-24 years) under modified constant routine conditions. The expression of hPer1 as determined by real-time PCR with gene-specific hybriprobes in MNCs and PMNs showed significant daily variations with similar acrophases and peak transcription in the subjective morning. The acrophases in hPer1 expression rhythms in MNCs and PMNs were found to correlate positively with that of the serum melatonin secretion rhythms, which is a reliable phase marker of the suprachiasmatic nucleus (SCN), the circadian master clock. The present findings indicate that clock gene activity could be preserved across different peripheral blood cell types and support the assumption that peripheral clocks are entrained by the SCN.

Stability of sleep timing against the melatonin secretion rhythm with advancing age: clinical implications.

Aging is often associated with decreased ability of sleep maintenance. It has been hypothesized that the elderly experience a delayed timing of sleep period relative to the circadian phase of various sleep-promoting physiological functions, possibly causing decreased sleep propensity in the latter part of their nocturnal sleep. We evaluated the relationship between the sleep timing and circadian phase of melatonin secretion, which is known as a possible human sleep modulator as well as a stable marker of biological clock phase (BCP). Actigraph sleep recordings were performed, followed by the evaluation of melatonin phase under dim light in 42 healthy elderly volunteers (mean age, 68.8 yr; male/female ratio, 16/26) and 27 healthy young male volunteers (22.5 yr). Elderly subjects showed remarkable clock time advances in both the midpoint of BCP and sleep timing, with a significant decrease in sleep maintenance ability. However, they showed no significant age-related changes in the sleep timing against the midpoint of BCP, suggesting that early morning awakening in the elderly appeared in a BCP for which sleep propensity remained sufficient to sustain sleep. The present findings do not support the hitherto known hypothesis that age-related delay in the sleep timing against the BCP induces the deterioration in sleep maintenance in the elderly.

Heat loss, sleepiness, and impaired performance after diazepam administration in humans.

In spite of the accumulation of knowledge regarding the neuropharmacological action of benzodiazepines (Bz), the physiological process by which their sedative/hypnotic effects are induced remains poorly understood. We conducted a single-blind, crossover trial to evaluate the role of the thermoregulatory process in sleepiness and impaired psychomotor performance induced by a standard Bz, diazepam (DZP). Each of the eight healthy young male volunteers (mean age, 19.75 years; range, 18-23 years) was given a single oral dose of either 5 or 10 mg of DZP or placebo 12 h after his average sleep onset time. Changes in plasma DZP concentration, proximal body temperature (p-BT), distal body temperature (d-BT), subjective sleepiness measured by the Visual Analog Scale and Stanford Sleepiness Scale, and psychomotor performance measured by Choice Reaction Time were monitored under a modified constant routine condition in which various factors affecting thermoregulation, alertness, and psychomotor performances were strictly controlled. Orally administered DZP induced a significant transient decrease in p-BT and psychomotor performance as well as an increase in d-BT and subjective sleepiness. Distal-p-BT gradient (DPG; difference between d-BT and p-BT), which is an indicator of blood flow in distal skin regions, showed a strong positive correlation with the plasma DZP concentration, indicating that DZP in clinical doses promotes heat loss in a dose-dependent manner. The DPG also correlated positively with the magnitude of subjective sleepiness and impaired psychomotor performance. These findings indicate that the sedative/hypnotic effects of Bz could be due, at least in part, to changes in thermoregulation, especially in the process of heat loss, in humans.