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. Key Points The side effects of prolonged benzodiazepine receptor agonist use are more common and/or severe in older adults who take multiple hypnotic drugs concomitantly. This study revealed that benzodiazepine receptor agonists are the most commonly prescribed first-line treatments and are mostly prescribed in the inpatient setting in hospital departments such as internal medicine, general surgery, orthopaedic surgery and urology. A melatonin receptor agonist and an orexin receptor antagonist were commonly prescribed to patients in an outpatient setting in internal medicine, psychiatry and neurology departments

Sleep Deprivation Influences Diurnal Variation of Human Time Perception with Prefrontal Activity Change: A Functional Near-Infrared Spectroscopy Study

Human short-time perception shows diurnal variation. In general, short-time perception fluctuates in parallel with circadian clock parameters, while diurnal variation seems to be modulated by sleep deprivation per se. Functional imaging studies have reported that short-time perception recruits a neural network that includes subcortical structures, as well as cortical areas involving the prefrontal cortex (PFC). It has also been reported that the PFC is vulnerable to sleep deprivation, which has an influence on various cognitive functions. The present study is aimed at elucidating the influence of PFC vulnerability to sleep deprivation on short-time perception, using the optical imaging technique of functional near-infrared spectroscopy. Eighteen participants performed 10-s time production tasks before (at 21:00) and after (at 09:00) experimental nights both in sleep-controlled and sleep-deprived conditions in a 4-day laboratory-based crossover study. Compared to the sleep-controlled condition, one-night sleep deprivation induced a significant reduction in the produced time simultaneous with an increased hemodynamic response in the left PFC at 09:00. These results suggest that activation of the left PFC, which possibly reflects functional compensation under a sleep-deprived condition, is associated with alteration of short-time perception

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 monoversus 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

Prevalence of childhood obstructive sleep apnea syndrome and its role in daytime sleepiness

ObjectivesTo investigate childhood obstructive sleep apnea syndrome (OSAS) and its role in daytime sleepiness among school-age children.MethodsA questionnaire survey was conducted with 25,211 children aged 6–15 (mean, 10.39) years attending 148 elementary and 71 middle schools in 10 prefectures across Japan and their parents. Questions concerned 4 sleep habit items (bedtime, sleep onset latency, wake time after sleep onset, wake-up time) and 4 sleep disorder items (loud snoring, snorts/gasps, breathing pauses, seems very sleepy in the daytime). Total sleep time (TST) was calculated with sleep habits. Severe possible OSAS (p-OSAS) was defined as having loud snoring, snorts and gasps, or breathing pauses “frequently” (≥ 5 times per week), and mild p-OSAS was rated as having any of these “sometimes” (2–4 times per week). Severe daytime sleepiness was defined as seeming very sleepy “frequently” and mild daytime sleepiness as seeming very sleepy “sometimes”.ResultsMean prevalence of mild to severe p-OSAS and severe p-OSAS in children across all grade levels was 9.5% and 1.6%, respectively. p-OSAS was particularly prevalent in children at lower elementary levels, decreasing with advancing grade levels. Prevalence of mild and severe daytime sleepiness was 6.1% and 0.9%, respectively, among all children (7.0%). Prevalence of daytime sleepiness increased with advancing grade levels, particularly in middle-school level. Average TST was 8.4 ± 2.2 h in both elementary and middle-school levels, and decreased as grades advanced, particularly in middle-school levels. Multivariate logistic regression analysis showed that middle-school level, TST < 8 h, and p-OSAS were independent factors for daytime sleepiness. Strong correlations were found between severe daytime sleepiness and severe p-OSAS or TST < 6 h, and between daytime sleepiness and loud snoring or breathing pauses.Conclusionp-OSAS may be an independent factor influencing daytime sleepiness in school-age children. Loud snoring and breathing pauses could be clinical markers for children with severe daytime sleepiness

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

Prevalence of childhood obstructive sleep apnea syndrome and its role in daytime sleepiness

Objectives To investigate childhood obstructive sleep apnea syndrome (OSAS) and its role in daytime sleepiness among school-age children. Methods A questionnaire survey was conducted with 25,211 children aged 6-15 (mean, 10.39) years attending 148 elementary and 71 middle schools in 10 prefectures across Japan and their parents. Questions concerned 4 sleep habit items (bedtime, sleep onset latency, wake time after sleep onset, wake-up time) and 4 sleep disorder items (loud snoring, snorts/gasps, breathing pauses, seems very sleepy in the daytime). Total sleep time (TST) was calculated with sleep habits. Severe possible OSAS (p-OSAS) was defined as having loud snoring, snorts and gasps, or breathing pauses frequently (>= 5 times per week), and mild p-OSAS was rated as having any of these sometimes (2-4 times per week). Severe daytime sleepiness was defined as seeming very sleepy frequently and mild daytime sleepiness as seeming very sleepy sometimes. Results Mean prevalence of mild to severe p-OSAS and severe p-OSAS in children across all grade levels was 9.5% and 1.6%, respectively. p-OSAS was particularly prevalent in children at lower elementary levels, decreasing with advancing grade levels. Prevalence of mild and severe daytime sleepiness was 6.1% and 0.9%, respectively, among all children (7.0%). Prevalence of daytime sleepiness increased with advancing grade levels, particularly in middle-school level. Average TST was 8.4 +/- 2.2 h in both elementary and middle-school levels, and decreased as grades advanced, particularly in middle-school levels. Multivariate logistic regression analysis showed that middle-school level, TST < 8 h, and p-OSAS were independent factors for daytime sleepiness. Strong correlations were found between severe daytime sleepiness and severe p-OSAS or TST < 6 h, and between daytime sleepiness and loud snoring or breathing pauses. Conclusion p-OSAS may be an independent factor influencing daytime sleepiness in school-age children. Loud snoring and breathing pauses could be clinical markers for children with severe daytime sleepiness

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\u27 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\u27 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

Single nucleotide polymorphism-based genome-wide linkage analysis in Japanese atopic dermatitis families

<p>Abstract</p> <p>Background</p> <p>Atopic dermatitis develops as a result of complex interactions between several genetic and environmental factors. To date, 4 genome-wide linkage studies of atopic dermatitis have been performed in Caucasian populations, however, similar studies have not been done in Asian populations. The aim of this study was to identify chromosome regions linked to atopic dermatitis in a Japanese population.</p> <p>Methods</p> <p>We used a high-density, single nucleotide polymorphism genotyping assay, the Illumina BeadArray Linkage Mapping Panel (version 4) comprising 5,861 single nucleotide polymorphisms, to perform a genome-wide linkage analysis of 77 Japanese families with 111 affected sib-pairs with atopic dermatitis.</p> <p>Results</p> <p>We found suggestive evidence for linkage with 15q21 (LOD = 2.01, NPL = 2.87, <it>P </it>= .0012) and weak linkage to 1q24 (LOD = 1.26, NPL = 2.44, <it>P </it>= .008).</p> <p>Conclusion</p> <p>We report the first genome-wide linkage study of atopic dermatitis in an Asian population, and novel loci on chromosomes 15q21 and 1q24 linked to atopic dermatitis. Identification of novel causative genes for atopic dermatitis will advance our understanding of the pathogenesis of atopic dermatitis.</p

Neural Network Development in Late Adolescents during Observation of Risk-Taking Action

Emotional maturity and social awareness are important for adolescents, particularly college students beginning to face the challenges and risks of the adult world. However, there has been relatively little research into personality maturation and psychological development during late adolescence and the neural changes underlying this development. We investigated the correlation between psychological properties (neuroticism, extraversion, anxiety, and depression) and age among late adolescents (n = 25, from 18 years and 1 month to 22 years and 8 months). The results revealed that late adolescents became less neurotic, less anxious, less depressive and more extraverted as they aged. Participants then observed video clips depicting hand movements with and without a risk of harm (risk-taking or safe actions) during functional magnetic resonance imaging (fMRI). The results revealed that risk-taking actions elicited significantly stronger activation in the bilateral inferior parietal lobule, temporal visual regions (superior/middle temporal areas), and parieto-occipital visual areas (cuneus, middle occipital gyri, precuneus). We found positive correlations of age and extraversion with neural activation in the insula, middle temporal gyrus, lingual gyrus, and precuneus. We also found a negative correlation of age and anxiety with activation in the angular gyrus, precentral gyrus, and red nucleus/substantia nigra. Moreover, we found that insula activation mediated the relationship between age and extraversion. Overall, our results indicate that late adolescents become less anxious and more extraverted with age, a process involving functional neural changes in brain networks related to social cognition and emotional processing. The possible neural mechanisms of psychological and social maturation during late adolescence are discussed

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