Elevated Brain-Derived Neurotrophic Factor Levels During Depressive Mixed States.

OBJECTIVE: Neurotrophin-like brain-derived neurotrophic factor (BDNF) and pro-inflammatory cytokines may modulate the pathophysiology of mood disorders. Although several studies show alterations in these biomarkers during the depressive, manic, and euthymic states of mood disorders, evidence is lacking for those in a mixed state. Therefore, this study aimed to investigate the relationship between the depressive mixed state (DMX) and peripheral neurobiological factors. METHODS: We enrolled 136 patients with major depressive episodes. Depressive symptoms were assessed using the Quick Inventory of Depressive Symptomatology Self-Report Japanese version (QIDS-SR-J). The severity of DMX was assessed using the self-administered 12-item questionnaire (DMX-12). Categorical screening as DMX-positive (n=54) was determined by a cutoff score of 13 or more in the specific eight symptoms from the DMX-12; the remaining were DMX-negative (n=82). Serum BDNF, tumor necrosis factor-α, highsensitivity C-reactive protein, and interleukin-6 levels were measured. RESULTS: When comparing biomarkers between the DMX-positive and DMX-negative groups, higher serum BDNF concentration in the DMX-positive group than in the DMX-negative group was the only significant finding (p=0.009). A positive correlation existed between the total score of the eight specific symptoms of DMX-12 and the BDNF concentration (r=0.190, p=0.027). After adjustment for confounders, logistic regression analysis revealed that BDNF (odds ratio [OR]=1.07, 95% confidence interval [CI]=1.00-1.14, p=0.045), bipolar diagnosis (OR=3.43, 95% CI=1.36-8.66, p=0.009), and total QIDS-SR-J score (OR=1.29, 95% CI=1.15-1.43, p<0.001) were significantly associated with DMX positivity. CONCLUSION: BDNF was positively associated with DMX severity, suggesting that higher BDNF concentrations may be involved in the pathophysiology of DMX.

Age-related cognitive decline is accelerated in alcohol use disorder.

This study aimed to examine potential cognitive impairments in patients with alcohol use disorder (AUD), and explore the factors affecting them. We recruited 97 inpatients with AUD, showing superficially normal cognitive function (mini-mental state examination score ≥24) for this study. We assessed cognitive function after a 4-week post-abstinence period using the Brief Assessment of Cognition in Schizophrenia-Japanese version (BACS-J). Relationships between BACS-J subcategory/composite raw scores and Z-scores (deviation from standard data in healthy Japanese) and background factors such as age, sex, education, smoking status, mini-mental state examination score, body mass index, systolic blood pressure, severity of depression, alcohol consumption, and laboratory findings were analyzed. Multiple regression analysis showed that the age (p < 0.001) and total bilirubin level (p = 0.014) were worsening factors for the BACS-J composite raw score, whereas education (p < 0.001) was a protective factor. An inverse correlation was apparent between the age and the composite Z-score of the BACS-J (r = -0.431, p < 0.001). Receiver operating characteristic (ROC) analysis identified 53 years as the cutoff age for predicting more than -2SD cognitive decline from the normal standard, with a high negative predictive value (95%). Patients with AUD aged ≥53 years showed more pronounced impairments in verbal memory, working memory, verbal fluency, and attention than those younger than 53 years (p < 0.05). These findings clearly demonstrate accelerated age-related cognitive decline in patients with AUD, especially those aged ≥53 years, suggesting the necessity of early intervention in patients with AUD to prevent progressive cognitive impairment and preserve their quality of life.

Combination Psychotropic Use for Schizophrenia With Long-Acting Injectable Antipsychotics and Oral Antipsychotics: A Nationwide Real-World Study in Japan.

BACKGROUND: Although several guidelines recommend monotherapy with antipsychotics for the treatment of schizophrenia, patients who receive long-acting injectable antipsychotics (LAIs) are frequently treated with oral antipsychotics (OAPs). In the present study, we investigated the detailed use of psychotropic medications among patients throughout Japan with schizophrenia who received LAIs or OAPs. METHODS: The present study used data from the project for the Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment from 94 facilities in Japan. The LAI group included patients who received any LAI, and the non-LAI group included patients who took only OAP medications at discharge. The participants of this study were 2518 schizophrenia patients (263 in the LAI group and 2255 in the non-LAI group) who received inpatient treatment and had prescription information at discharge between 2016 and 2020. RESULTS: This study revealed significantly higher rates of polypharmacy antipsychotics, number of antipsychotics, and chlorpromazine equivalents in the LAI group than in the non-LAI group. In contrast, the LAI group showed lower rate of concomitant use of hypnotic and/or antianxiety medication than the non-LAI group. CONCLUSIONS: Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group.

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.

Clozapine Treatment Is Associated With Higher Prescription Rate of Antipsychotic Monotherapy and Lower Prescription Rate of Other Concomitant Psychotropics: A Real-World Nationwide Study.

BACKGROUND: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine. METHODS: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary. RESULTS: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P < 2.0 × 10-16) and the ND-TRS without clozapine group (54.7%; P < 2.0 × 10-16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; P = 1.1 × 10-6) and the ND-TRS without clozapine group (17.0%; P = 5.9 × 10-6). CONCLUSIONS: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription.

Prescription of Anticholinergic Drugs in Patients With Schizophrenia: Analysis of Antipsychotic Prescription Patterns and Hospital Characteristics.

In several clinical guidelines for schizophrenia, long-term use of anticholinergic drugs is not recommended. We investigated the characteristics of the use of anticholinergics in patients with schizophrenia by considering psychotropic prescription patterns and differences among hospitals. A cross-sectional, retrospective prescription survey at the time of discharge was conducted on 2027 patients with schizophrenia from 69 Japanese hospitals. We examined the relations among psychotropic drug prescriptions regarding anticholinergic prescription. We divided the hospitals into three groups-low rate group (LG), medium rate group (MG), and high rate group (HG)-according to their anticholinergic prescription rates, and analyzed the relationship between anticholinergic prescription rates and antipsychotic prescription. Anticholinergic drugs were prescribed to 618 patients (30.5%), and the prescription rates were significantly higher for high antipsychotic doses, antipsychotic polypharmacy, and first-generation antipsychotics (FGAs) use. The anticholinergic prescription rate varied considerably among hospitals, ranging from 0 to 66.7%, and it was significantly higher in patients with antipsychotic monotherapy, antipsychotic polypharmacy, and normal and high doses of antipsychotics in HG than in those LG and MG. The anticholinergics prescription rate in patients with second-generation antipsychotic monotherapy in HG was also significantly higher than in those LG and MG; however, the difference was no longer significant in patients with FGA monotherapy. Conclusively, in addition to high antipsychotic doses, antipsychotic polypharmacy, and FGA use, hospital characteristics influence the prescribing of anticholinergic drugs.

Development of a 20-item questionnaire for drinking behavior pattern (DBP-20) toward personalized behavioral approaches for alcohol use disorder.

Although screening tools are available for alcohol use disorders (AUD), such as the Alcohol Use Disorders Identification Test (AUDIT), these tools do not directly characterize individual drinking behavior for patients with AUD. Therefore, the aim of this study was to develop a new self-report questionnaire to identify the characteristics of drinking behavior patterns in patients with AUD.The study team developed a self-administered 20-item questionnaire for drinking behavior pattern (DBP-20) based on semi-structured interviews of patients with AUD. The DBP-20 and AUDIT were administered to 232 patients with AUD and 222 normal drinkers (1 ≤ AUDIT <20) as controls. Exploratory factor analysis of the DBP-20 was conducted for patients with AUD, followed by comparisons of its item and subscale scores between patients with AUD and controls. Correlations of AUDIT with total and subscale scores of the DBP-20 were also analyzed. Receiver operating characteristic (ROC) analyses for the DBP-20 and its subscales were performed to distinguish patients with AUD from controls.Exploratory factor analysis revealed a multidimensional 4-factor model of the DBP-20: coping with negative affect, automaticity, enhancement, and social use. Significant differences in DBP-20 total and subscale scores were observed for patients with AUD versus controls for all factors, except the social use subscale. Both the coping with negative affect and automaticity subscale scores as well as total DBP-20 scores were highly correlated with AUDIT scores. Total DBP-20 scores showed the greatest sensitivity, negative predictive value, and area under the ROC curve to distinguish patients with AUD from normal drinkers.Drinking as a means of coping with negative affect and automaticity may be specific for patients with AUD. DBP-20 may help patients with AUD to be aware of their own targeted problematic drinking behaviors and to seek their personalized behavioral approaches in a collaborative relationship with therapists.

The characteristics of patients receiving psychotropic pro re nata medication at discharge for the treatment of schizophrenia and major depressive disorder: A nationwide survey from the EGUIDE project.

BACKGROUND: Although several guidelines indicate that daily pharmacotherapy is an important part of the treatment of schizophrenia and major depressive disorder, there are few reports regarding pro re nata (PRN) prescriptions. The purpose of this study is to clarify the characteristics of patients receiving psychotropic PRN prescription for the treatment of schizophrenia and major depressive disorder. METHOD: We used data from 'the effectiveness of guideline for dissemination and education in psychiatric treatment' (EGUIDE) project to evaluate the presence or absence of psychotropic PRN prescription at the time of discharge, the age and sex of patients receiving PRN prescription for each diagnosis, and the association between PRN prescription and regular daily psychotropics. RESULTS: The psychotropic PRN prescription ratio was 29.9% among 2617 patients with schizophrenia and 31.1% among 1248 patients with major depressive disorder at discharge. In schizophrenia, the psychotropic PRN prescription ratio was 21.6% for patients aged 65 years or older, which was lower than that of all other age groups. In major depressive disorder, the psychotropic PRN prescription ratio was 34.2% for female patients, which was significantly higher than that for male patients (25.5%). In schizophrenia, there was an association between psychotropic PRN prescription and regular use of multiple psychotropic medications. CONCLUSIONS: Psychotropic PRN prescription was less common in elderly patients with schizophrenia and more common in female patients with major depressive disorder. In schizophrenia, psychotropic PRN prescription led to polypharmacy of psychotropics. Further studies are needed to accumulate evidence and to provide education on appropriate PRN prescriptions.

A Cross-Sectional Study of Evening Hyperphagia and Nocturnal Ingestion: Core Constituents of Night Eating Syndrome with Different Background Factors.

This web-based cross-sectional survey aimed to elucidate the differences between the two core symptoms of night eating syndrome (NES): evening hyperphagia and nocturnal ingestion in the general Japanese population aged 16-79 years. Participants who consumed at least 25% of daily calories after dinner were defined as having evening hyperphagia. Those who consumed food after sleep initiation at least twice a week were determined to have nocturnal ingestion. Of the 8348 participants, 119 (1.5%) were categorized in the evening hyperphagia group, 208 (2.6%) in the nocturnal ingestion group, and 8024 in the non-NES group. Participants with evening hyperphagia and nocturnal ingestion had significantly higher anxiety scores (p < 0.05 and p < 0.001, respectively) and depression (p < 0.001 for both) than those without NES. Multiple logistic regression analysis revealed that evening hyperphagia was significantly and independently associated with higher body mass index, shorter sleep duration, later sleep-wake schedule, and higher insomnia score, while nocturnal ingestion was significantly and independently associated with younger age, smoking habit, living alone, earlier sleep-wake schedule, and higher insomnia score. Sleep duration and sleep-wake schedule characteristics in the two groups were opposite, suggesting differences in the sleep pathophysiology mechanisms.

Characteristics of discharge prescriptions for patients with schizophrenia or major depressive disorder: Real-world evidence from the Effectiveness of Guidelines for Dissemination and Education (EGUIDE) psychiatric treatment project.

BACKGROUND: Monopharmacy with antipsychotics and antidepressants is the first-line treatment for schizophrenia and major depressive disorder (MDD) in most clinical guidelines, while polypharmacy with psychotropic agents in the treatment of schizophrenia is common in clinical practice. There are no detailed data on the prescription patterns for inpatients with mental illness with reliable diagnoses made by treating psychiatrists. METHODS: We gathered prescription data at discharge from 2177 patients with schizophrenia and 1238 patients with MDD from October 2016 to March 2018. RESULTS: The patients with schizophrenia aged between 60 and 79 were prescribed lower doses of antipsychotics and hypnotics/anxiolytics than those aged between 40 and 59. There were significant differences between the prescription rate of antipsychotics in the patients with schizophrenia and that of antidepressants in the patients with MDD. The frequency of concomitant drugs such as anti-Parkinson drugs, anxiolytics/hypnotics and mood stabilizers in the subjects with schizophrenia prescribed antipsychotic polypharmacy was significantly higher than that with monotherapy. For the patients with schizophrenia, olanzapine, risperidone, aripiprazole, quetiapine, and blonanserin were the five most prescribed antipsychotics. For the patients with MDD, mirtazapine, duloxetine, escitalopram, trazodone and sertraline were the five most prescribed antidepressants. CONCLUSIONS: Our results showed the use of high doses of antipsychotics, high percentages of antipsychotic polypharmacy and concurrent use of hypnotics/anxiolytics in patients with schizophrenia. Notably, these data were collected before intensive instruction regarding the guidelines; therefore, we need to assess the change in the prescription pattern post guideline instruction.

Prescription patterns in patients with schizophrenia in Japan: First-quality indicator data from the survey of "Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE)" project.

BACKGROUND: Guideline for Pharmacological Therapy for Schizophrenia was published by the Japanese Society of Neuropsychopharmacology in 2015. "Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment (EGUIDE)" project aimed to standardize medical practice using quality indicators (QIs) as indices to evaluate the quality of medical practice. In this study, we have reported the quality indicator values of prescription before the beginning of the guideline lectures in the EGUIDE project to ascertain the baseline status of treating patients with schizophrenia. METHODS: A cross-sectional, retrospective case record survey was conducted, involving 1164 patients with schizophrenia at the time of discharge. We checked all types and dosage of psychotropic drugs. RESULTS: Forty-three percent of patients had antipsychotic polypharmacy, and substantial concomitant medication was observed (antidepressants; 8%, mood stabilizers: 37%, anxiolytics or hypnotics: 68%). CONCLUSIONS: In the results obtained in this study, we plant to report changes in the effectiveness of education in the EGUIDE project near the future.

Ability of suvorexant to prevent delirium in patients in the intensive care unit: a randomized controlled trial.

AIM: There are no effective, tolerable, and established medications for preventing delirium in critically ill patients admitted to the intensive care unit (ICU). We investigated whether suvorexant was effective in preventing ICU delirium. METHODS: This randomized controlled study evaluated 70 adult patients (age ≥20 years) admitted to the mixed medical ICU of the Tokyo Medical University Hospital (Tokyo, Japan) between May 2015 and February 2017. Patients were randomized using a sealed envelope method to receive either suvorexant (n = 34; 15 mg for elderly patients and 20 mg for younger adults) or conventional treatment (n = 36) for a 7-day period. The primary outcome was delirium incidence based on the definition in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders. RESULTS: No significant between-group differences were observed in the demographic or clinical characteristics. Kaplan-Meier estimates revealed that time to delirium onset was significantly longer in the suvorexant group than in the conventional group (P < 0.05). CONCLUSION: Suvorexant might be effective in preventing delirium in ICU patients.

Later sleep schedule and depressive symptoms are associated with usage of multiple kinds of hypnotics.

OBJECTIVE: Usage of high doses of hypnotics possibly causes various adverse events. However, the risk factors of using multiple kinds of hypnotics have been inconclusive. To clarify this, we conducted a web-based cross-sectional questionnaire survey on the Japanese adult population. METHODS: A cross-sectional Internet-linked survey was conducted on 10,016 individuals and 1030 participants (10.3%) having subjective insomnia proceeded to subsequent analyses. The analyzed subjects were categorized into non-users of hypnotics (n = 833; 80.9%), users of a single kind of hypnotic (n = 96; 9.3%), and users of multiple kinds of hypnotics (n = 101; 9.8%). The descriptive variables including demographic data, scores of Center for Epidemiological Studies Depression Scale (CES-D), Short Form-8 Health-Related Quality of Life [QOL (SF-8)], Pittsburgh Sleep Quality Index (PSQI), and other parameters were compared among the groups. RESULTS: The users of multiple kinds of hypnotics had the highest mean score of CES-D, the lowest mental component summary of QOL (SF-8), and the latest sleep schedule among the three groups (p < 0.001). Logistic regression analyses revealed that sex (female: OR = 2.38; p < 0.001) and age (≥43 years old: OR = 2.61; p < 0.001) were independently associated with use of a single kind of hypnotic, while later sleep schedule (midpoint of sleep ≥5:30 a.m.: OR = 2.26; p < 0.001) and higher CES-D score (≥16 points: OR = 2.41; p < 0.001) were independently associated with use of multiple kinds of hypnotics. CONCLUSIONS: Characteristics of users of multiple kinds of hypnotics were different from those of users of a single kind of hypnotic.

Impact of hypnotics use on daytime function and factors associated with usage by female shift work nurses.

OBJECTIVE: We investigated quality of life (QOL) and work performance of hypnotics users, and explored the factors associated with multiple hypnotics usage in shift work nurses. METHODS: We conducted a questionnaire-based, cross-sectional survey on nurses in university hospitals. We analyzed responses from 1202 nurses; 997 were female shift work nurses (82.9%), including 696 and 281 two- and three-shift workers, respectively. RESULTS: The rate of hypnotics use was 10% (6.9% were single hypnotic users and 3.1% were multiple hypnotics users). The rate of insomnia did not differ between the single and multiple hypnotics users. However, multiple hypnotics users showed lower QOL, more severe depressive symptoms, and greater frequencies of work-related errors than those using a single hypnotic. A multiple logistic regression analysis revealed that age ≥27 years, presence of depression, eveningness chronotype, and presence of insomnia symptoms were significantly associated with hypnotics use. On the other hand, only the existence of shift work disorder (SWD) was significantly associated with usage of multiple hypnotics. CONCLUSIONS: The present study suggested that usage of multiple hypnotics is not beneficial for relieving insomnia or for keeping better QOL in shift work nurses. It would be desirable to explore the causal relationship between SWD and multiple hypnotics use in a future longitudinal study.