Effects of Japanese policies and novel hypnotics on long-term prescriptions of hypnotics.

AIM: The current study aimed to examine the effect of Japanese policies for appropriate hypnotics use and novel hypnotics (e.g. melatonin receptor agonist and orexin receptor antagonist [ORA]) on long-term prescriptions of hypnotics. METHODS: This retrospective study was conducted using a large-scale health insurance claims database. Among subscribers prescribed hypnotics at least once between April 2005 and March 2021, those prescribed hypnotics for the first time after being included in the database in three periods (period 1: April 2012-March 2013; period 2: April 2016-March 2017; and period 3: April 2018-March 2019) were eligible. These were set considering the timing of the 2014 and 2018 medical fee revisions (2014 for polypharmacy of three or more hypnotics, 2018 for long-term prescription of benzodiazepine receptor agonists for >12 months). The duration of consecutive prescriptions of hypnotics over 12 months was evaluated. Factors associated with short-term prescriptions of hypnotics were also investigated. RESULTS: In total, 186 535 participants were newly prescribed hypnotics. The mean duration of prescriptions was 2.9 months, and 9.3% of participants were prescribed hypnotics for 12 months. Prescription periods were not associated with short-term prescriptions of hypnotics. ORA use was associated with short-term prescriptions of hypnotics (adjusted hazard ratio, 1.077 [95% confidence interval, 1.035-1.120]; P < 0.001), but melatonin receptor agonist use was not. CONCLUSION: Japanese policies had no statistically significant effect on long-term prescriptions of hypnotics. Although this study suggests initiating ORA for insomniacs as a candidate strategy to prevent long-term prescriptions of hypnotics, further research is necessary to draw conclusions.

Patterns of hypnotic prescribing for residual insomnia and recurrence of major depressive disorder: a retrospective cohort study using a Japanese health insurance claims database.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent in Japan and frequently accompanied by insomnia that may persist even with MDD remission. Hypnotics are used for the pharmacological treatment of insomnia, but their influence on MDD recurrence or residual insomnia following MDD remission is unclear. This retrospective, longitudinal, cohort study utilized a large Japanese health insurance claims database to investigate patterns of hypnotic prescriptions among patients with MDD, and the influence of hypnotic prescription pattern on MDD recurrence. METHODS: Eligible patients (20-56 years) were those registered in the Japan Medical Data Center database between 1 January 2005 and 31 December 2018, and prescribed antidepressant and hypnotic therapy after being diagnosed with MDD. Patients who had ceased antidepressant therapy for > 180 days were followed for 1 year to evaluate depression recurrence, as assessed using Kaplan-Meier estimates. Logistic regression modelling was used to analyze the effect of hypnotic prescription pattern on MDD recurrence. RESULTS: Of the 179,174 patients diagnosed with MDD who initiated antidepressant treatment between 1 January 2006 and 30 June 2017, complete prescription information was available for 2946 eligible patients who had been prescribed hypnotics. More patients were prescribed hypnotic monotherapy (70.8%) than combination therapy (29.2%). The most prescribed therapies were benzodiazepine monotherapy (26.2%), non-benzodiazepine monotherapy (28.9%), and combination therapy with two drugs (21.1%). Among patients prescribed multiple hypnotics, concomitant prescriptions for anxiolytics, antipsychotics, mood stabilizers and sedative antidepressants were more common. The 1-year recurrence rate for MDD was approximately 20%, irrespective of hypnotic mono- versus combination therapy or class of hypnotic therapy. Being a spouse (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03-2.02) or other family member (OR, 1.46, 95% CI, 0.99-2.16) of the insured individual, or being prescribed a sedative antidepressant (OR, 1.50, 95% CI, 1.24-1.82) conferred higher odds of MDD recurrence within 1 year of completing antidepressant therapy. CONCLUSIONS: Benzodiazepines are the most prescribed hypnotic among Japanese patients with MDD, though combination hypnotic therapy is routinely prescribed. Hypnotic prescription pattern does not appear to influence real-world MDD recurrence, though hypnotics should be appropriately prescribed given class differences in efficacy and safety.

Impact of sleep problems on daytime function in school life: a cross-sectional study involving Japanese university students.

BACKGROUND: The aims of this study were 1) to clarify the prevalence of sleep problems (insomnia, insufficient sleep, and delayed sleep-wake phase) among Japanese university students; 2) to examine sociodemographic characteristics, lifestyle, and sleep-related symptoms in each sleep problem; and 3) to evaluate the association between the above-mentioned sleep problems and daytime dysfunction in school life. METHODS: Self-report questionnaire surveys were conducted at eight universities in Japan, and we received 1034 valid answers (78% female). The questionnaire consisted of socio-demographic characteristics, information on lifestyle, sleep pattern, sleep-related symptoms, and daytime dysfunction in school life. Groups with insomnia, behaviorally induced insufficient sleep syndrome (BIISS), delayed sleep-wake phase (DSWP), and BIISS + DSWP were defined. To identify the association between sleep problems and daytime dysfunction in school life, the generalized linear mixed effect model was conducted. RESULTS: Sleep duration on weekdays was 5.9 ± 1.2 h, and 38.2% of the students had a sleep duration < 6.0 h. About 16% of the students were categorized as evening-type individuals. More than half of the students (56.1%) had excessive daytime sleepiness. Insomnia was associated with tardiness (aOR: 0.8, 95%CI: 0.7-0.9) and falling asleep during class (aOR: 1.6: 95%CI: 1.4-2.0). BIISS was associated with tardiness (aOR: 1.5, 95%CI: 1.1-2.2) and interference with academic achievement (aOR: 1.9, 95%CI: 1.3-2.6). DSWP and BIISS + DSWP were associated with absence (aOR: 3.4, 95%CI: 2.2-5.1 / aOR: 4.2, 95%CI: 3.2-5.6), tardiness (aOR: 2.7, 95%CI: 1.8-4.1 / aOR: 2.2, 95%CI: 1.6-2.8), falling asleep during class (aOR: 2.6, 95%CI: 1.4-4.8 / aOR: 7.6, 95%CI: 3.3-17.2), and interference with academic achievement (aOR: 2.6, 95%CI: 1.7-3.9 / aOR: 2.1, 95%CI: 1.6-2.8). CONCLUSIONS: Students with DSWP and BIISS + DSWP were significantly associated with daytime dysfunction in school life, i.e. absence, tardiness, falling asleep during class and interference with academic achievement. Students displaying BIISS + DSWP were considered to have a relatively more serious condition compared with those with only insomnia, DSWP, or BIISS. It is therefore of utmost importance that university students aim to prevent DSWP and BIISS which were associated with daytime function in school life.

Sleepiness induced by sleep-debt enhanced amygdala activity for subliminal signals of fear.

BACKGROUND: Emotional information is frequently processed below the level of consciousness, where subcortical regions of the brain are thought to play an important role. In the absence of conscious visual experience, patients with visual cortex damage discriminate the valence of emotional expression. Even in healthy individuals, a subliminal mechanism can be utilized to compensate for a functional decline in visual cognition of various causes such as strong sleepiness. In this study, sleep deprivation was simulated in healthy individuals to investigate functional alterations in the subliminal processing of emotional information caused by reduced conscious visual cognition and attention due to an increase in subjective sleepiness. Fourteen healthy adult men participated in a within-subject crossover study consisting of a 5-day session of sleep debt (SD, 4-h sleep) and a 5-day session of sleep control (SC, 8-h sleep). On the last day of each session, participants performed an emotional face-viewing task that included backward masking of nonconscious presentations during magnetic resonance scanning. RESULTS: Finally, data from eleven participants who were unaware of nonconscious face presentations were analyzed. In fear contrasts, subjective sleepiness was significantly positively correlated with activity in the amygdala, ventromedial prefrontal cortex, hippocampus, and insular cortex, and was significantly negatively correlated with the secondary and tertiary visual areas and the fusiform face area. In fear-neutral contrasts, subjective sleepiness was significantly positively correlated with activity of the bilateral amygdala. Further, changes in subjective sleepiness (the difference between the SC and SD sessions) were correlated with both changes in amygdala activity and functional connectivity between the amygdala and superior colliculus in response to subliminal fearful faces. CONCLUSION: Sleepiness induced functional decline in the brain areas involved in conscious visual cognition of facial expressions, but also enhanced subliminal emotional processing via superior colliculus as represented by activity in the amygdala. These findings suggest that an evolutionally old and auxiliary subliminal hazard perception system is activated as a compensatory mechanism when conscious visual cognition is impaired. In addition, enhancement of subliminal emotional processing might cause involuntary emotional instability during sleep debt through changes in emotional response to or emotional evaluation of external stimuli.

Rhythmic expression of circadian clock genes in human leukocytes and beard hair follicle cells.

Evaluating individual circadian rhythm traits is crucial for understanding the human biological clock system. The present study reports characterization of physiological and molecular parameters in 13 healthy male subjects under a constant routine condition, where interfering factors were kept to minimum. We measured hormonal secretion levels and examined temporal expression profiles of circadian clock genes in peripheral leukocytes and beard hair follicle cells. All 13 subjects had prominent daily rhythms in melatonin and cortisol secretion. Significant circadian rhythmicity was found for PER1 in 9 subjects, PER2 in 3 subjects, PER3 in all 13 subjects, and BMAL1 in 8 subjects in leukocytes. Additionally, significant circadian rhythmicity was found for PER1 in 5 of 8 subjects tested, PER2 in 2 subjects, PER3 in 6 subjects, and BMAL1 in 3 subjects in beard hair follicle cells. The phase of PER1 and PER3 rhythms in leukocytes correlated significantly with that of physiological rhythms. Our results demonstrate that leukocytes and beard hair follicle cells possess an endogenous circadian clock and suggest that PER1 and PER3 expression would be appropriate biomarkers and hair follicle cells could be a useful tissue source for the evaluation of biological clock traits in individuals.

Increased cerebral blood flow in the right frontal lobe area during sleep precedes self-awakening in humans.

BACKGROUND: Some people can subconsciously wake up naturally (self-awakening) at a desired/planned time without external time stimuli. However, the underlying mechanism regulating this ability remains to be elucidated. This study sought to examine the relationship between hemodynamic changes in oxyhemoglobin (oxy-Hb) level in the prefrontal cortex and sleep structures during sleep in subjects instructed to self-awaken. RESULTS: Fifteen healthy right-handed male volunteers with regular sleep habits participated in a consecutive two-night crossover study. The subjects were instructed to wake up at a specified time ("request" condition) or instructed to sleep until the morning but forced to wake up at 03:00 without prior notice ("surprise" condition). Those who awoke within ± 30 min of the planned waking time were defined as those who succeeded in self-awakening ("success" group). Seven subjects succeeded in self-awakening and eight failed.No significant differences were observed in the amounts of sleep in each stage between conditions or between groups. On the "request" night, an increase in oxy-Hb level in the right prefrontal cortex and a decrease in δ power were observed in the "success" group around 30 min before self-awakening, whereas no such changes were observed in the "failure" group. On the "surprise" night, no significant changes were observed in oxy-Hb level or δ power in either group. CONCLUSIONS: These findings demonstrate a correlation between self-awakening and a pre-awakening increase in hemodynamic activation in the right prefrontal cortex, suggesting the structure's contribution to time estimation ability.

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.

Alpha activity during rem sleep contributes to overnight improvement in performance on a visual discrimination task.

The purpose of this preliminary study was to clarify the association between cortical and subcortical activities during REM and non-REM sleep with overnight improvement of performance on a procedural memory task. Eleven healthy volunteers (M age = 23.8 yr., SD = 3.1) participated in this study which was conducted over two consecutive nights: an adaptation night and the experimental night. They underwent a visual discrimination task before and after the experimental night. A positive correlation was observed between overnight performance improvement on the visual discrimination task and EEG alpha band power during REM sleep, while no significant correlation was observed between the performance and either the amount of Stage REM sleep, REM activity, or other sleep variables. The findings corroborate other studies and suggest that cortical activity during REM sleep contributed to procedural memory consolidation and highlights the importance of measuring quantitative REM sleep components to elucidate the role of physiological sleep on memory consolidation in humans.

Validity of an algorithm for determining sleep/wake states using FS-760 in school-aged children.

BACKGROUND: Actigraphy is a method used for determining sleep (S)/wakefulness (W) by actigraph, a device equipped with a built-in accelerometer and an algorithm validated for each device. The S/W determination algorithm for the waist-worn actigraph FS-760 has been formulated for adults. However, the algorithm for children has not been established. The purpose of this study was to formulate an algorithm for discriminating S/W in school-aged children using FS-760 and to evaluate its validity. We further tested the generalizability of existing algorithm for adults by applying it to the children's activity data and then examined factors associated with adult algorithm agreement rates by multiple regression analysis using combined adult and children data. METHODS: Sixty-five, healthy, school-aged children (aged 6 to 15 years) were recruited and randomly assigned to two groups: A (n = 33) and B (n = 32). They underwent 8-h polysomnography (PSG) and wore FS-760 simultaneously to obtain activity data. To determine the central epoch of the sleep/wake states (𝑥), a five-order linear discriminant analysis was conducted using the activity intensity of group A for five epochs (𝑥-2, 𝑥-1, 𝑥, 𝑥+1, 𝑥+2; 10 min) and evaluate its accuracy with the activity of group B. To reveal the factors associated with adult algorithm agreement rate, we integrated the activity, age, sleep efficiency of 15 adults (aged 20 to 39 years) and those of 65 children for multiple regression analysis. RESULTS: The mean agreement rate of the developed algorithm was 91.0%, with a mean sensitivity (true sleep detection rate) of 93.0% and a mean specificity (true wakefulness detection rate) of 63.9%. The agreement rate of the adult algorithm applied to children's activity was significantly lower (81.8%) than that of the children algorithm. Multiple regression analysis showed that the agreement rates calculated by the adult algorithm were significantly related to mean activity of the 𝑥 epoch in NREM and REM sleep as well as age and sleep efficiency. CONCLUSIONS: The S/W states in school-aged children can be reliably assessed using the developed algorithm for waist-worn actigraph FS-760. Since the accuracy of the adult algorithms decreased when applied it to children which have different activity levels during sleep, the establishment and validation of population-specific S/W algorithms should be required.

Prescribing Pattern of Hypnotic Medications in Patients Initiating Treatment at Japanese Hospitals: A Nationwide, Retrospective, Longitudinal, Observational Study Using a Claims Database.

BACKGROUND: Prolonged treatment of insomnia using benzodiazepine (BZD) receptor agonists, including BZD and non-BZD hypnotic drugs, can cause drug dependence, tolerance, abuse and other adverse events. These side effects are more common and/or severe in older adults taking different hypnotic drugs concomitantly. Therefore, a single prescription is limited to 30 daily doses for most BZD receptor agonists and restrictions apply to the prescription of more than three types of hypnotic drugs in Japan. Little is known, however, about the real-world prescribing pattern of hypnotic drugs in Japan. OBJECTIVE: We analysed prescribing patterns for hypnotic drugs in Japan to evaluate whether real-world use differs from guideline recommendations. METHODS: In this nationwide, retrospective, longitudinal, observational study, we analysed the types of hypnotic drugs prescribed, duration of medication and treatment setting in a subset of hospitals in Japan using a hospital-based administrative claims database (Medical Data Vision). Patients initiating treatment with hypnotic drugs between January 2012 and December 2016 were included in the analyses to assess the duration of medication and occurrence of co-prescription of a second and third hypnotic drug, within a year from prescription of the first hypnotic drugs. RESULTS: In 261,167 patients analysed, the first hypnotic drugs prescribed were BZDs (59.7%), non-BZDs (36.8%), a melatonin receptor agonist [MRA] (3.1%) and an orexin receptor antagonist [ORA] (0.4%). Benzodiazepine and non-BZD hypnotic drugs were mostly prescribed in inpatient settings (57.7% and 63.0%, respectively) and the MRA and ORA mostly in outpatient settings (62.6% and 65.4%, respectively). The departments that prescribed the most patients their first hypnotic drugs were internal medicine (23.6%), general surgery (11.8%), orthopaedic surgery (11.4%) and urology (5.3%). Of the total prescriptions of MRA and ORA as the first hypnotic drugs, 22.0% and 31.8% were in internal medicine, 4.4% each in general surgery, 6.0% and 4.5% in orthopaedic surgery, 9.7% and 4.4% in neurology, and 10.1% and 12.2% in psychiatry departments, respectively. Mean duration of medication was 1.13 months for non-BZDs, 1.15 months for BZDs, 1.29 months for the ORA and 1.83 months for the MRA. Overall, 5.3% (95% confidence interval 5.2-5.4) of patients were prescribed a second hypnotic drug; of these, 8.4% (95% confidence interval 8.0-8.9) were prescribed at least three hypnotic drugs within a year. Patients who were prescribed three or more hypnotic drugs received higher doses of the first drug than patients who received fewer hypnotic drugs. CONCLUSIONS: Benzodiazepine receptor agonists were the most common hypnotic drugs prescribed as the first drug to patients in Japan. Further education and awareness may be needed on the risk of complications and adverse events associated with these therapies. The duration of BZD receptor agonist use was shorter than for the MRA and ORA, in accordance with prescribing guidelines. Long-term use and co-prescribing of hypnotic drugs were also uncommon.

Risk factors for low adherence to methylphenidate treatment in pediatric patients with attention-deficit/hyperactivity disorder.

Poor adherence is a major concern in the treatment of attention-deficit/hyperactivity disorder (ADHD). The objective of this study was to evaluate factors linked to early interruption of and low adherence to treatment with osmotic-release oral system methylphenidate hydrochloride (OROS-MPH) in pediatric patients with ADHD. A total of 1353 young people (age 6-17 years) with a diagnosis of ADHD who newly started OROS-MPH were extracted from the pharmacoepidemiological data of 3 million people in Japan. The cohort was retrospectively surveyed every month for 12 months. Ten possible risk factors were extracted from the data and analyzed by multivariable logistic regression. Sensitivity analysis was conducted to ensure the robustness of the analysis. The results revealed that treatment adherence was generally poor, with a tendency for discontinuation in the early stage. Multivariable logistic regression results showed that adherence is reduced by female sex, lower starting dose, and concomitant atomoxetine or hypnotics. These findings may help clinicians to predict the risk of poor adherence in the early stage of treatment and improve not only patients' symptoms, but also their quality of life.

Effect of residual insomnia and use of hypnotics on relapse of depression: a retrospective cohort study using a health insurance claims database.

BACKGROUND: Residual insomnia is associated with a risk of depression recurrence. METHODS: In this retrospective, longitudinal cohort study, the recurrence pattern of depression in patients with or without residual insomnia was assessed using a health insurance claims database. Patients who were diagnosed with major depressive disorder and prescribed antidepressants, between January 2006 and June 2017 in Japan, were enrolled in the study. Residual insomnia was defined by a prescription of hypnotics, and recurrence of depression by prescription of antidepressants. Main outcomes included time to recurrence and the 1-year recurrence rate. Factors associated with recurrence of depression were assessed by multivariate analyses. The effect of residual insomnia on the frequency of recurrence was assessed by Chi-square test. RESULTS: Of the 30,381 patients analyzed, there were 4,166 and 26,215 patients with or without residual insomnia, respectively. Time to recurrence in patients with residual insomnia was significantly shorter compared with those without residual insomnia (p <0.001), with a 1-year recurrence rate (95% CI) of 43.4% (41.9-45.0) and 7.4% (7.1-7.7), respectively. The frequency of recurrence was significantly higher in patients with residual insomnia than in those without (p <0.0001). A higher risk of depression recurrence (odds ratio 9.98, 95% CI 9.22-10.81) was found for residual insomnia compared with other significant factors. LIMITATIONS: The diagnosis stated in the receipt data may not accurately reflect the patient's condition, and medication adherence was unknown but assumed. CONCLUSIONS: Residual insomnia is a significant risk factor for depression recurrence in Japanese patients.

Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire.

AIMS: Benzodiazepine receptor agonists (BZ-RAs) are frequently prescribed to treat insomnia; however, their long-term use is not recommended. To introduce an appropriate pharmaco-therapy, the current state and background factors of BZ-RAs' dependence must be elucidated. In this study, we developed a Japanese version of the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ-J) and conducted a study of BZ-RAs' use disorder. METHODS: The Bendep-SRQ-J was created with permission from the original developer. Subjects were inpatients and outpatients receiving BZ-RAs between 2012 and 2013. Clinical data collected were Bendep-SRQ-J scores, sleep disorders for which BZ-RAs were prescribed, physical comorbidities, psychotropic drugs, and lifestyle factors. Logistic analysis was performed to extract factors associated with severe symptoms. RESULTS: Of the 707 patients prescribed BZ-RAs, 324 had voluntarily tapered or discontinued their drugs. Logistic analysis showed that the total number of drugs administered in the last 6 months correlated with both worsening of symptoms or conditions. This was more notable among younger patients, and the proportion of patients with severe symptoms or conditions increased with the increasing number of drugs. CONCLUSION: Using the Bendep-SRQ-J, we elucidated the current state of BZ-RA dependence. Nearly half of the patients were non-compliant. The proportion of patients with severe symptoms or disease conditions increased with the increase in the number of drugs administered. These findings highlight the need for clinicians to be aware of the likelihood of benzodiazepine dependence, especially in young patients and patients prescribed multiple hypnotics.

Clinical characteristics of Japanese patients with familial obstructive sleep apnoea syndrome.

BACKGROUND AND OBJECTIVE: Craniofacial structure and body fat are key factors that predispose to upper airway obstruction while asleep, and these phenotypes can be genetically inherited. Neither the clinical characteristics of familial obstructive sleep apnoea syndrome (OSAS) nor the definitive morphological factors responsible for familial occurrence have been well identified. This study compared the clinical and cephalographic characteristics of Japanese patients with familial OSAS, non-familial OSAS and healthy controls, to clarify the mechanisms underlying familial OSAS. METHODS: The study recruited 28 patients with familial OSAS, comprising 14 index cases and 14 first-degree relatives affected with OSAS, and compared these with age- and sex-matched patients with non-familial OSAS (n = 32) and healthy subjects (n = 33). Data on clinical status were collected, including the presence of hypertension, BMI and daytime sleepiness measured on the Epworth sleepiness scale. Respiratory function was evaluated by the AHI, % periods in which SpO(2) fell 90% or below and lowest value of SpO(2) on polysomnograms. Information on the first witnessed age of habitual snoring during sleep was collected via interview with patients and/or their family members. A detailed cephalometric assessment was made of each study subject. RESULTS: Patients with familial OSAS had lower mean BMI than did patients with non-familial OSAS. The first witnessed age of habitual snoring was younger in the familial cases than the non-familial cases. Cephalometric variables showed that the posterior airway space and the distance between the gonion and the gnathion were significantly smaller in the familial group than in the other two groups. CONCLUSIONS: Familial OSAS occurred at a younger age than non-familial OSAS due to minor anomalies of craniofacial morphology.

Relationship between late-life depression and life stressors: large-scale cross-sectional study of a representative sample of the Japanese general population.

AIM: The purpose of the present study was to clarify the relationship between late-life depression and daily life stress in a representative sample of 10 969 Japanese subjects. METHODS: Data on 10 969 adults aged > or =50 who participated in the Active Survey of Health and Welfare in 2000, were analyzed. The self-administered questionnaire included items on 21 reasons for life stressors and the magnitude of stress, as well as the Japanese version of the Center for Epidemiologic Studies Depression Scale (CES-D). The relationship between the incidence of life stressors and mild-moderate (D(16)) and severe (D(26)) depressive symptoms was examined using logistic regression analysis. RESULTS: A total of 21.9% of subjects had D(16) symptoms, and 9.3% had D(26) symptoms. Further, increased age and being female were associated with more severe depressive state. Logistic regression analysis indicated that the strongest relationship between both the incidence of D(16) and D(26) symptoms and life stressors stemmed from 'having no one to talk to' (odds ratio = 3.3 and 5.0, respectively). Late-life depression was also associated with 'loss of purpose in life', 'separation/divorce', 'having nothing to do', 'health/illness/care of self', and 'debt'. CONCLUSION: There is a relationship between late-life depression and diminished social relationships, experiences involving loss of purpose in life or human relationships, and health problems in the Japanese general population.

Long-term use of hypnotics: Analysis of trends and risk factors.

OBJECTIVE: Patients with chronic insomnia are prone to long-term use of hypnotics. Reported risk factors include aging, female sex, and comorbid psychiatric disorders. However, most previous studies have been cross-sectional cohort studies. METHOD: We conducted a retrospective cohort study using medical service payment data for 330,000 people to determine the duration of prescription of hypnotics and the risk factors for long-term use. We followed up 3981 patients (2382 M, 1599 F, age 40.3 ± 12.4 years) who were prescribed hypnotics for the first time between April 2005 and March 2008. RESULTS: Of these 3981 patients, 59.6% were prescribed hypnotics for only 1 month, 11.3% were prescribed hypnotics for 2 consecutive months, and 10.1% of patients continued receiving prescriptions for the entire 12-month observation period. In multiple logistic time-dependent Cox analyses, use of antidepressants, mean dose of hypnotics, and advanced age were significantly associated with long-term use of hypnotics (p < 0.01). In an analysis of the association between long-term use of hypnotics and prescribed dosage, high monthly dose, advanced age, and department of first visit were significantly associated with long-term use (p < 0.01). CONCLUSION: These clinical indicators may be effective for early identification of patients with insomnia who are at high risk of developing physical dependence on hypnotics.

Association Between the Use of Antidepressants and the Risk of Type 2 Diabetes: A Large, Population-Based Cohort Study in Japan.

OBJECTIVE: This study aimed to reveal the associations between the risk of new-onset type 2 diabetes and the duration of antidepressant use and the antidepressant dose, and between antidepressant use after diabetes onset and clinical outcomes. RESEARCH DESIGN AND METHODS: In this large-scale retrospective cohort study in Japan, new users of antidepressants (exposure group) and nonusers (nonexposure group), aged 20-79 years, were included between 1 April 2006 and 31 May 2015. Patients with a history of diabetes or receipt of antidiabetes treatment were excluded. Covariates were adjusted by using propensity score matching; the associations were analyzed between risk of new-onset type 2 diabetes and the duration of antidepressant use/dose of antidepressant in the exposure and nonexposure groups by using Cox proportional hazards models. Changes in glycated hemoglobin (HbA1c) level were examined in groups with continuous use, discontinuation, or a reduction in the dose of antidepressants. RESULTS: Of 90,530 subjects, 45,265 were in both the exposure and the nonexposure group after propensity score matching; 5,225 patients (5.8%) developed diabetes. Antidepressant use was associated with the risk of diabetes onset in a time- and dose-dependent manner. The adjusted hazard ratio was 1.27 (95% CI 1.16-1.39) for short-term low-dose and 3.95 (95% CI 3.31-4.72) for long-term high-dose antidepressant use. HbA1c levels were lower in patients who discontinued or reduced the dose of antidepressants (F[2,49] = 8.17; P < 0.001). CONCLUSIONS: Long-term antidepressant use increased the risk of type 2 diabetes onset in a time- and dose-dependent manner. Glucose tolerance improved when antidepressants were discontinued or the dose was reduced after diabetes onset.

Clinical characteristics of restless legs syndrome in end-stage renal failure and idiopathic RLS patients.

This study was done to identify the clinical characteristics of uremic restless legs syndrome (RLS). Consecutive uremic RLS patients (n = 15) and idiopathic RLS patients (iRLS; n = 20) were evaluated. The groups were compared with respect to their clinical course, subjective symptoms [using the Pittsburgh Sleep Quality Index (PSQI) and the International Restless Legs Syndrome Severity Scale (IRLS)], polysomnographic (PSG) variables, the results of the suggested immobilization test (SIT), and the drug doses used to treat RLS. The duration of the disorder was significantly shorter in the uremic RLS group than in the iRLS group. The PSQI and IRLS scores before treatment were higher in the uremic RLS group than in the iRLS group. The periodic leg movement index (PLM index) on PSG and the SIT index were also higher in the uremic RLS group (P < 0.001, respectively). The bromocriptine equivalent dose of dopaminergic agonists used to treat RLS was significantly higher in the uremic RLS group (P < 0.001). Uremic RLS appears to deteriorate faster and to become more severe than iRLS. Moreover, uremic RLS patients appear to have a decreased response to dopaminergic agonists.

Inter-individual difference in pupil size correlates to suppression of melatonin by exposure to light.

There are large inter-individual differences in pupil size and suppression of melatonin by exposure to light. It has been reported that melatonin suppression by exposure to light increases when pupils are pharmacologically dilated. However, the correlation between normal inter-individual difference in pupil size and melatonin suppression by exposure to light is not clear. Twenty-three healthy male subjects (22.6+/-2.7 years old) were exposed to light (1000 lx) for 2 h at night. The starting time of exposure to light was set to the ascending phase of melatonin concentration of each subject. Pupil area and saliva melatonin concentration were measured before exposure to light under dim light (15 lx) and during exposure to light. There were large inter-individual differences in melatonin suppression and pupil area. The mean and standard deviation of percentage of melatonin suppression 2 h after exposure to light was 57.2+/-22.1%. The mean and standard deviation of pupil areas before and 2 h after exposure to light were 30.7+/-7.9 mm2 and 15.9+/-4.8 mm2, respectively. The percentage of melatonin suppression by light was positively correlated with pupil area during light exposure (r=0.525, p<0.02). Interestingly, it was also correlated with pupil area measured before exposure to light, under dim light (15 lx) (r=0.658, p<0.001). These results suggest that inter-individual difference in pupil area positively correlates with melatonin suppression by light and that pupil area under dim light is a predictor of inter-individual differences in melatonin suppression by light.