Delayed Sleep Phase Syndrome Patients Research Articles

Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation.

ObjectivesDelayed sleep phase syndrome (DSPS) is a chronic dysfunction of circadian rhythm of the subject that impairs functioning in social, occupational, or other spheres. High rate of depression is found among DSPS patients. Aripiprazole (APZ), a second-generation antipsychotic, is effective in treatment of depression as well as schizophrenia. Recently, few case reports show the effectiveness of APZ in treating DSPS and non-24-hour sleep–wake rhythm disorder. Therefore, we tried to treat DSPS with depression using APZ.MethodsTwelve subjects (including four women) aged 19–64 years were included. The subjects were prescribed initially 0.5–3 mg of APZ once a day with subsequent dose adjustments.ResultsSleep onset, midpoint of sleep, and sleep offset were significantly advanced by 1.1, 1.8, and 2.5 hours, respectively. Unexpectedly, sleep duration became significantly shorter by 1.3 hours after treatment. Their depressive moods showed an unremarkable change.ConclusionLow dose of APZ advanced the sleep rhythm and reduced nocturnal sleep time in the subjects with DSPS. Since it is not easy for physicians to treat prolonged sleep duration often associated with DSPS, this medication would become a new therapeutic option for these patients.

Relation between morningness–eveningness score and depressive symptoms among patients with delayed sleep phase syndrome

Depressive symptoms are observed in a relatively large series of patients with delayed sleep phase syndrome (DSPS). This study was undertaken to investigate the prevalence, characteristics, and factors associated with depressive symptoms among DSPS patients. This study targeted 90 consecutive patients (54 men, 27.1±9.2 years old) diagnosed as having DSPS. Demographic and clinical characteristics were assessed at their initial visit, including application of the Zung self-rating depression scale (SDS) and morningness-eveningness questionnaire. A series of logistic regression analyses were conducted to determine the factors associated with depressive symptoms (determined as SDS⩾48). Sixty-four percent of the DSPS patients were in a moderate or severe depressive state. Diurnal variation, sleep disturbance, fatigue, and psychomotor retardation were the main depressive symptom items on SDS in the DSPS patients. Logistic regression analyses showed that SDS⩾48 was significantly associated with moderate and definite evening chronotype. In contrast, self-reported nocturnal sleep onset and offset times were not associated with depressive symptoms. There is a high prevalence of depressive symptoms among the DSPS patients. The symptomatic structure of depressive symptoms in this population appears to differ from those of typical depression. Moreover, results of our study suggest that depressive symptoms are more associated with the preference of the evening chronotype rather than sleep-wake phase among DSPS patients.

Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome

Background Depression is a common problem in patients with Delayed Sleep Phase Syndrome (DSPS). This study used a randomized, double-blind, crossover, placebo-controlled approach to test the hypothesis that exogenous melatonin (5 mg) can attenuate depressive symptomatology in DSPS patients. Methods Twenty patients with an established diagnosis of DSPS were dichotomized into DSPS with depressive symptoms (Group I; n = 8) and without depressive symptoms (Group II; n = 12) based on structured clinical interviews and a score greater than 17 on Center for Epidemiologic Studies Depression Scale (CES-D). Both groups received melatonin and placebo treatment for 4 weeks with a 1-week washout period in between. Participants underwent a clinical interview and psychometric evaluation to assess depression, and overnight polysomnographic sleep studies were carried out at baseline and at the end of melatonin and placebo treatments. Furthermore, melatonin secretion rhythm as a circadian phase marker was assessed by measuring urinary 6-sulphatoxymelatonin levels. Results Melatonin treatment significantly reduced depression scores in the depressed patients as measured by the CES-D and Hamilton Depression Rating Scale – 17. Melatonin treatment improved sleep continuity in both groups compared to placebo and baseline conditions. Group I individuals showed marked alterations in melatonin rhythms compared to Group II individuals. Conclusion Exogenous melatonin treatment may be an effective treatment modality for individuals with circadian rhythm sleep disorders and associated comorbid depressive symptomatology.

Sleep timing and circadian phase in delayed sleep phase syndrome.

Delayed sleep phase syndrome (DSPS) is a circadian rhythm sleep disorder in which the timing of the sleep episode occurs later than desired and is associated with difficulty falling asleep, problems awakening on time (e.g., to meet work or school obligations), and daytime sleepiness. The phase relationship between the timing of sleep and endogenous circadian rhythms is critical to the initiation and maintenance of sleep, and significant alteration leads to impairment of sleep quality and duration. The aim of this retrospective study was to determine the phase relationship between sleep-wake times and physiological markers of circadian timing in clinic patients with DSPS. Objective and subjective measures of sleep timing and circadian phase markers (core body temperature and melatonin) were measured in patients with DSPS and compared with age-matched controls. As expected, significant delays in the timing of the major sleep episode and circadian phase of body temperature and melatonin rhythms were seen in the DSPS group when allowed to sleep at their own habitual schedules, but the phase relationship between sleep-wake times and circadian phase was similar between the 2 groups. These results suggest that the symptoms of insomnia and excessive daytime sleepiness in DSPS patients living under entrained real-life conditions cannot be explained by an alteration in the phase relationship between sleep-wake patterns and other physiological circadian rhythms.

Clinical efficacy of dim light melatonin onset testing in diagnosing delayed sleep phase syndrome

Background Delayed Sleep Phase Syndrome (DSPS) arises from biological clock desynchrony and accounts for 10% of chronic insomnia patients. Currently DSPS is diagnosed based on sleep/wake cycle disruptions rather than examining the underlying biological clock alterations. The objective of the study was to determine the sensitivity and specificity of the Dim Light Melatonin Onset (DLMO) Test in diagnosing DSPS in a clinical setting. Methods Fifty-six patients (mean age 28 years) symptomatic of DSPS participated in the study. Following an initial assessment of DSPS using sleep diaries, participants underwent two consecutive nights of polysomnography (PSG), with an imposed sleep period on the second night to demonstrate the delay in the timing of habitual sleep period and to thereby confirm DSPS. Circadian phase delays were also measured using melatonin secretion profiles, and the efficacy of diagnosing DSPS using DLMO was compared to using sleep diaries and PSG. Melatonin secretion was assayed for each individual by ELISA using saliva samples. Results Main outcome measures included the time of melatonin secretion onset, clinical sensitivity and specificity of the DLMO test. The time of melatonin secretion onset was significantly delayed in DSPS patients. Clinical sensitivity and specificity of the DLMO test in diagnosing DSPS were 90.3% and 84.0%, respectively. Conclusions The DLMO test is an accurate tool for differentiating between sleep disorder patients with or without underlying circadian rhythm disruption. It is effective for phase typing DSPS patients in a clinical setting.

The G619A Aa-nat Gene Polymorphism does not Contribute to Sleep Time Variation in the Brazilian Population

Genes involved in melatonin synthesis, such as Aa-nat, may be important for our understanding of diurnal preference and circadian rhythm disturbances in humans. In Japan, Hohjoh et al. reported increased allelic frequencies of the 619A allele of the G619A Aa-nat gene polymorphism in a sample of Delayed Sleep Phase Syndrome (DSPS) patients. The present study sought to analyze G619A polymorphism frequency in a Brazilian sample, including DSPS patients. We found almost no allelic variation for G619A polymorphism in our sample, except for two heterozygous samples out of 551. Our results leave open the question of whether there would be an association if there were some genetic variation in our population. It is important to analyze different ethnic groups in order to validate the effect of G619A polymorphism on sleep timing.

Psychological characteristics and the efficacy of hospitalization treatment on delayed sleep phase syndrome patients with school refusal

The study investigated the efficacy of the treatment of patients with delayed sleep phase syndrome (DSPS) through hospitalization, given social cues and their psychological characteristics, using a picture-frustration study. The participants were 22 DSPS patients with school refusal during adolescence, consisting of 13 boys and 9 girls (mean age ± SD = 16.0 ± 1.4, range = 13–18). Over 90% of the DSPS patients with school refusal showed improvements in their sleep-wake rhythm (S-W) just after hospitalization. Over 50% of them maintained their improved S-W after discharge and attended school. The picture-frustration study for DSPS patients with school refusal, especially in patients who showed no improvement in their S-W and school refusal after discharge, showed low aggression, low expression of their dissatisfaction, high suppression of their emotion, low social interest and high self-criticism. Patients who did not show improvement in their S-W through hospitalization have psychological problems such as those mentioned above. They may therefore need to take psychological intervention such as self-assertion training.

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

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. 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. Sleep disorders unit in National Center Hospital. 11 DSPS patients and 11 age-matched healthy volunteers. N/A. 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. 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.

A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference.

To investigate the link between extreme diurnal preference, delayed sleep phase syndrome, and a length polymorphism in Per3. Subjects were genotyped using polymerase chain reaction. Subjects with defined diurnal preference as determined by the Horne-Ostberg questionnaire and patients with delayed sleep phase syndrome. The Per3 polymorphism correlated significantly with extreme diurnal preference, the longer allele associating with morningness and the shorter allele with eveningness. The shorter allele was strongly associated with the delayed sleep phase syndrome patients, 75% of whom were homozygous. The length of the Per3 repeat region identifies a potential genetic marker for extreme diurnal preference.

The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects.

Mutations in clock genes are associated with abnormal circadian parameters, including sleep. An association has been reported previously between a polymorphism (3111C), situated in the 3'-untranslated region (3'-UTR) of the circadian gene Clock and evening preference. In the present study, this polymorphism was assessed in: (1) 105 control subjects with defined diurnal preference, (2) 26 blind subjects with free-running circadian rhythms and characterized with regard to circadian period (tau) and (3) 16 delayed sleep phase syndrome patients. The control group was chosen from a larger population (n = 484) by Horne-Ostberg questionnaire analysis, from which three subgroups were selected (evening, intermediate and morning preference). Data from sleep diaries completed by 90% of these subjects showed a strong correlation between preferred and estimated timings of sleep and wake. The mean timings of activities for the evening group were at least 2 h later than the morning group. Genetic analysis showed that, in contrast with the previously published finding, there was no association between 3111C and eveningness. Neither was there an association between 3111C and tau, nor a significant difference in 3111C frequency between the normal and delayed sleep phase syndrome groups. To assess the effect of this polymorphism on messenger RNA (mRNA) translatability, luciferase reporter gene constructs containing the two Clock polymorphic variants in their 3'-UTR were transfected into COS-1 cells and luciferase activity measured. No significant difference was observed between the two variants. These results do not support Clock 3111C as a marker for diurnal preference, tau, or delayed sleep phase syndrome in humans.

A PEDIGREE OF ONE FAMILY WITH DELAYED SLEEP PHASE SYNDROME

The prevalence of delayed sleep phase syndrome (DSPS) has been estimated to be quite low. Although no genetic inheritance pattern has been described, it has been reported that close to 50% of DSPS patients have biological relatives with similar symptoms. A pedigree of one extended family with symptoms suggestive of DSPS has been identified. Morningnesseveningness questionnaires were administered to all first- and second-degree relatives of a proband identified with DSPS. A total of 51 (86%) questionnaires were returned, and 6 adult biological relatives of 27 (22%) showed a preference for eveningness, which is much higher than reported in the general population. Both the paternal and maternal branches contained affected individuals, suggesting the possibility of a bilineal mode of inheritance. While the trait did not obey simple Mendelian inheritance, the vertical patterns of transmission were consistent with either an autosomal dominant mode of inheritance with incomplete penetrance or a multifactorial mode of inheritance. These data provide some preliminary support to the notion that eveningness, and thus DSPS, may have a genetic component. The prevalence of symptoms suggestive of DSPS is higher in this family than reported in the general population. Case reports such as this support the utility of larger, more systematic studies. It is unclear whether this degree of familiarity is representative of that in the general population. (Chronobiology International, 18(5), 831–840, 2001)

Altered phase relation between sleep timing and core body temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep–wake syndrome in humans

Changes in the phase relation between sleep timing and the circadian pacemaker are suspected to have an etiological significance in circadian rhythm sleep disorders. Simultaneous recordings of rest-activity and rectal temperature in seven sighted delayed sleep phase syndrome (DSPS) patients, seven sighted non-24-h sleep–wake syndrome (non-24) patients, and 14 healthy controls were made for 10–14 days continuously in the subjects’ homes. We found that sleep length and the interval from the body temperature (BT) trough to sleep offset were significantly longer in both non-24 and DSPS patients than in the controls, and that the interval between sleep onset and the BT trough was significantly less in the non-24 patients than in the DSPS patients and the controls. We postulate these alterations in phase relation to be associated with phase changes of the circadian pacemaker via different illumination timings.

Predisposing factors in delayed sleep phase syndrome.

We classified 64 patients with chronic delayed sleep phase syndrome (DSPS) into the primary (n = 53) and secondary (n = 11) group according to presence or absence of such signs as difficulty in waking up which appeared much earlier than the onset of DSPS. The age at the onset of the early signs concentrated in adolescence. The familial occurrence of DSPS was noted in 11 patients of the primary group. In human leukocyte antigen (HLA) typing, the incidence of DR1 positivity alone was significantly higher in DSPS patients than in healthy subjects. Minnesota Multiphasic Personality Inventory revealed high scores on depression, psychoasthenia and hypochondriasis. We suggest that a predisposition to DSPS includes biological, genetic, social and psychological factors, various combinations of which may lead to DSPS.

Poor Compensatory Function for Sleep Loss as a Pathogenic Factor in Patients with Delayed Sleep Phase Syndrome

Delayed sleep phase syndrome (DSPS) is a condition in which the patient is unable to reset or phase-advance his/her sleep timing properly after transient sleep delay and consequently shows persistent sleep phase delay. Prior studies suggested that DSPS is associated with a phase delay in the circadian pacemaker, but there was no evidence to explain the patient's inability to reset sleep phase. We used an ultra-short sleep-wake schedule together with simultaneous measurement of dim light melatonin rhythm after 24-hour sleep deprivation to allow the differential observation of diurnal sleep propensity fluctuation both from circadian and homeostatic aspects in 11 patients with DSPS (17-37 years; 8 men, 3 women) and 15 healthy controls (19-32 years; 8 men, 7 women). NA. NA. NA. DSPS patients showed less ability to compensate for previous sleep loss during their circadian day and first hours of their circadian nighttime determined by dim light melatonin onset compared with controls, while controls compensated for previous sleep loss at most circadian times. Though shapes of dim light melatonin rhythm did not differ between the groups, phase angle between melatonin and sleep propensity rhythms was wider in DSPS patients than in controls. These findings suggest that poor compensatory function for sleep loss predisposes DSPS patients to failure to reset their sleep phase. Our results provide implications for understanding not only the pathophysiology of DSPS but also the biological basis for why some people can change their sleep schedule easily according to personal or social demands while others cannot.

Effects of melatonin on the quality of life in patients with delayed sleep phase syndrome

Objective: The purpose of this study was to compare health-related quality of life of delayed sleep phase syndrome (DSPS) patients with a random Dutch sample and four samples of patients with other chronic conditions. We also investigated the effectiveness of treatment with 5 mg of melatonin on the quality of life of DSPS patients. Methods: Forty-three DSPS patients completed a quality-of-life questionnaire (Medical Outcome Study Short Form-36 [MOS SF-36] health survey) just before and 2–9 months after participation in a clinical trial involving the administration of melatonin. Scores were compared with responses to the same survey by a random Dutch sample and by patients with sleep apnea, clinical depression, migraine, and osteoarthritis. Results: MOS SF-36 scales scores were significantly lower in DSPS patients relative to age- and gender-adjusted norms for the Dutch sample. Some health dimensions were more affected, and others less affected, by DSPS compared with the other chronic conditions. Melatonin treatment improved all scales except the scale “role due to emotional problems.” Conclusion: DSPS has a unique significant quality-of-life burden that seems to be improved by treatment with melatonin.

Possible association of human leucocyte antigen DR1 with delayed sleep phase syndrome.

The study investigated the human leucocyte antigen (HLA), types A, B and DR, of 42 patients with delayed sleep phase syndrome (DSPS) and compared the frequencies of the antigens with those in 117 healthy controls. The comparison revealed that the gene frequencies and positivities of HLA-A, -B and -DR, except for DR1, had no significant differences between the patients and controls. The frequency of HLA-DR1 was increased in the DSPS patients as compared with that in the healthy controls (P = 0.0069 in positivity). Although the corrected P-value (0.069) for multiple comparisons almost reached the significance level, the results indicated a possible association of the HLA-DR1 antigen with DSPS. This study suggests that there are genetic predispositions to DSPS.

Poor recovery sleep after sleep deprivation in delayed sleep phase syndrome.

To clarify disturbances in sleep regulation in patients with delayed sleep phase syndrome (DSPS), we studied three patients with DSPS and seven healthy controls. Sleep propensity and melatonin rhythms after 24-h sleep deprivation were investigated under dim light condition by using the ultra-short sleep-wake schedule. The sleep propensity curves displayed clear differences between DSPS patients and the controls. During the subjective day when melatonin was not produced, recovery sleep after the sleep deprivation did not occur in DSPS patients, while recovery sleep occurred during the subjective day in controls. This suggests that DSPS may involve problems related to the homeostatic regulation of sleep after sleep deprivation.

Effects of phototherapy in patients with delayed sleep phase syndrome.

Phototherapy was given to six patients with delayed sleep phase syndrome (DSPS). Polysomnography (PSG) and core body temperature were examined before and after phototherapy. Phototherapy was administered to each patient for 5 days, and this treatment not only advanced the delayed sleep phase but also delayed the time of minimum body temperature in all patients. On the PSG, decreases in total sleep time and amounts of stages 2 and REM were observed after phototherapy. These results suggest that phototherapy is effective even in the short term in advancing delays in sleep phase and time of minimum body temperature in DSPS patients.

Melatonin rhythms in delayed sleep phase syndrome.

The aim of this study was to compare circadian and sleep characteristics between patients with delayed sleep phase syndrome (DSPS) and healthy controls. The authors studied 8 DSPS patients and 15 normal controls. Serum melatonin concentration was assessed every hour for 24 h under dim light conditions. The sleep phase and the melatonin rhythm in DSPS patients were significantly delayed compared to those in normal controls. Sleep length was significantly greater in DSPS patients compared to that in controls, but the duration of melatonin secretion did not differ between the two groups. The final awakening, relative to melatonin onset, melatonin midpoint, and melatonin offset, was significantly longer in DSPS patients than in controls. By contrast, the timing of sleep onset relative to melatonin rhythm did not differ between the two groups. The authors found a significant positive correlation between sleep phase markers and melatonin phase markers in DSPS. They postulate that a delayed circadian pacemaker may be responsible for delayed sleep phase syndrome. The alteration of phase angle between melatonin rhythm and sleep phase suggested that not only the delay of the circadian clock but also a functional disturbance of the sleep-wake mechanism underlies DSPS.

Evaluating the Role of Melatonin in the Long-Term Treatment of Delayed Sleep Phase Syndrome (DSPS)

Delayed sleep phase syndrome (DSPS) involves a mismatch between the usual daily schedule required by the individual's environment and his or her circadian sleep-wake pattern. Patients suffering from DSPS are treated with chronotherapy, light therapy, or melatonin administration. While chro-notherapy and light therapy are demanding and difficult treatments that usually lead to compliance problems, melatonin administration is a relatively simple and easy treatment option. Previous studies carried out on relatively small samples of DSPS patients have shown that melatonin has a sleep-promoting and entraining action when taken in the evening. The present study, which accompanied routine treatment in our sleep clinic, examined the efficiency of melatonin treatment in a relatively large population of DSPS subjects by means of subjective reports. The 61 subjects, 37 males and 24 females, were diagnosed with DSPS by means of clinical assessment and actigraphy at our sleep clinic. Their mean pretreatment falling asleep and waking times were 03: 09 (SD = 86.22 minutes) and 11: 31 (SD = 98.58 minutes), respectively. They were treated with a 6-week course of 5 mg of oral melatonin taken daily at 22: 00. A survey questionnaire was sent to the home of each subject 12–18 months after the end of the treatment; the survey investigated the efficiency of the melatonin treatment and its possible side effects. Of the patients, 96.7% reported that the melatonin treatment was helpful, with almost no side effects. Of these, 91.5% reported a relapse to their pretreatment sleeping patterns within 1 year of the end of treatment. Only 28.8% reported that the relapse occurred within 1 week. The pretreatment falling asleep and waking times of patients in whom the changes were retained for a relatively long period of time were significantly earlier than those of patients whose relapse was immediate (t = 2.18, p <. 05; t = 2.39, p <. 05, respectively), with no difference in sleep duration. The implications of these findings, as well as further research possibilities, are discussed.