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

Cavernous malformation of the optic chiasm with continuous hemorrhage in a pregnant woman: A case report

Background Cavernous malformation of the anterior visual pathway is rare, especially in pregnant woman. Planning a treatment strategy with cross-disciplinary specialists is important. Case description A 27-year-old pregnant woman presented with acute hemorrhage around the right optic nerve and chiasm, manifesting as poor vision in both eyes. Examination revealed right-eye deteriorated acuity and bilateral temporal hemianopsia. Computed tomography showed an oval high-density mass in the suprasellar region. Gradient echo-based T2-weighted magnetic resonance imaging showed the lesion to be hypointense (possibly a hematoma) and mainly in the optic chiasm. Fluid attenuated inversion recovery imaging showed a bilateral optic tract surrounding the lesion, which enlarged over 1 week, increasing the loss of visual function. Five days after admission, she delivered a healthy >2500-g baby by cesarean section (CS). Right frontotemporal craniotomy was performed 7 days after CS. Incision of the right optic nerve's lateral surface revealed clotted blood with abnormal vascular construction from the right side of the chiasm. We removed the hematoma and vascular lesion. Visual evoked potentials were detected only after optic chiasm decompression. Histological evaluation revealed a hematoma-like lesion with capsules and hemosiderin deposition, suggesting cavernous malformation. Her postoperative recovery was uneventful, with right visual acuity returning to normal, and her visual field not deteriorating any more. Conclusion Devising a treatment strategy with the obstetrician was important in this case to manage the hematoma and cavernous malformation safely

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

Decreased activity in the reward network of chronic insomnia patients

In modern society, many people have insomnia. Chronic insomnia has been noted as a risk factor for depression. However, there are few functional imaging studies of the brain on affective functions in chronic insomnia. This study aimed to investigate brain activities induced by emotional stimuli in chronic insomnia patients. Fifteen patients with primary insomnia and 30 age and gender matched healthy controls participated in this study. Both groups were presented images of fearful, happy, and neutral expressions consciously and non-consciously while undergoing MRI to compare the activity in regions of the brain responsible for emotions. Conscious presentation of the Happy-Neutral contrast showed significantly lower activation in the right orbitofrontal cortex of patients compared to healthy controls. The Happy-Neutral contrast presented in a non-conscious manner resulted in significantly lower activation of the ventral striatum, right insula, putamen, orbitofrontal cortex and ventral tegmental area in patients compared to healthy controls. Our findings revealed that responsiveness to positive emotional stimuli were decreased in insomniac patients. Specifically, brain networks associated with rewards and processing positive emotions showed decreased responsiveness to happy emotions especially for non-conscious image. The magnitude of activity in these areas also correlated with severity of insomnia, even after controlling for depression scale scores. These findings suggest that insomnia induces an affective functional disorder through an underlying mechanism of decreased sensitivity in the regions of the brain responsible for emotions and rewards to positive emotional stimuli

Recovery from Unrecognized Sleep Loss Accumulated in Daily Life Improved Mood Regulation via Prefrontal Suppression of Amygdala Activity

Many modern people suffer from sleep debt that has accumulated in everyday life but is not subjectively noticed [potential sleep debt (PSD)]. Our hypothesis for this study was that resolution of PSD through sleep extension optimizes mood regulation by altering the functional connectivity between the amygdala and prefrontal cortex. Fifteen healthy male participants underwent an experiment consisting of a baseline (BL) evaluation followed by two successive interventions, namely, a 9-day sleep extension followed by one night of total sleep deprivation (TSD). Tests performed before and after the interventions included a questionnaire on negative mood and neuroimaging with arterial spin labeling MRI for evaluating regional cerebral blood flow (rCBF) and functional connectivity. Negative mood and amygdala rCBF were significantly reduced after sleep extension compared with BL. The amygdala had a significant negative functional connectivity with the medial prefrontal cortex (FCamg–MPFC), and this negative connectivity was greater after sleep extension than at BL. After TSD, these indices reverted to the same level as at BL. An additional path analysis with structural equation modeling showed that the FCamg–MPFC significantly explained the amygdala rCBF and that the amygdala rCBF significantly explained the negative mood. These findings suggest that the use of our sleep extension protocol normalized amygdala activity via negative amygdala–MPFC functional connectivity. The resolution of unnoticed PSD may improve mood by enhancing frontal suppression of hyperactivity in the amygdala caused by PSD accumulating in everyday life

Potential of Genome-Wide Studies in Unrelated Plus Trees of a Coniferous Species, Cryptomeria japonica (Japanese Cedar)

A genome-wide association study (GWAS) was conducted on more than 30,000 single nucleotide polymorphisms (SNPs) in unrelated first-generation plus tree genotypes from three populations of Japanese cedar Cryptomeria japonica D. Don with genomic prediction for traits of growth, wood properties and male fecundity. Among the assessed populations, genetic characteristics including the extent of linkage disequilibrium (LD) and genetic structure differed and these differences are considered to be due to differences in genetic background. Through population-independent GWAS, several significant SNPs found close to the regions associated with each of these traits and shared in common across the populations were identified. The accuracies of genomic predictions were dependent on the traits and populations and reflected the genetic architecture of traits and genetic characteristics. Prediction accuracies using SNPs selected based on GWAS results were similar to those using all SNPs for several combinations of traits and populations. We discussed the application of genome-wide studies for C. japonica improvement

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362