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Objectives: To evaluate the short-term efficacy and safety of blonanserin in adolescents with schizophrenia.Methods: This 6-week multicenter, double-blind, randomized, placebo-controlled study investigated fixed-dose blonanserin (8 or 16 mg/day) in patients 12-18 years of age diagnosed with schizophrenia, as indicated by a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 and a Clinical Global Impressions-Severity score of >= 3. The primary endpoint was change from baseline to week 6 in the PANSS total score, using a mixed model for repeated measures analysis. Safety was assessed by the incidence and severity of adverse events (AEs).Results: Among 151 randomized patients, 150 were included in the primary analysis population. Demographic and clinical characteristics were similar across groups at baseline. The rate of study discontinuation was 14.9%, 23.5%, and 28.3% in patients administered with placebo, blonanserin 8 mg/day, and blonanserin 16 mg/day, respectively. The least-squares mean change (95% confidence interval [CI]) from baseline to week 6 in PANSS total score was -10.6 (-16.10 to -5.10), -15.3 (-20.80 to -9.86), and -20.5 (-25.89 to -15.16) in patients administered placebo, 8 mg/day blonanserin, and 16 mg/day blonanserin, respectively. The 16-mg/day blonanserin group showed significantly greater reduction in the PANSS total score than the placebo group (least-squares mean difference [95% CI]: -9.9 [-17.61 to -2.25], p = 0.012, effect size: 0.538), although the 8-mg/day group showed no significant difference. The incidence of AEs such as akathisia, somnolence, and hyperprolactinemia was higher in the blonanserin groups than in the placebo group. AEs associated with blonanserin were generally mild and were consistent with its known profile in adults with schizophrenia.Conclusions: Blonanserin achieved a sufficient efficacy in adolescent patients, and the safety profile was similar to that in adults, which suggests that blonanserin may be a safe treatment option for adolescents with schizophrenia.Study registration number: Japic CTI-111724.

Objectives: To evaluate the long-term efficacy and safety/tolerability of oral blonanserin in adolescents with schizophrenia (Study registration number: JapicCTI-111725). Methods: This 52-week, mul...

Background The current study evaluated the long-term (52 week) safety and impact on symptom measures of lurasidone (with or without lithium or valproate) for the treatment of bipolar I disorder in Japanese patients. Methods Bipolar patients for this open-label flexibly dosed lurasidone (20–120 mg/day) study were recruited from those with a recent/current depressive episode who completed an initial 6 week, double-blind, placebo-controlled, lurasidone study (depressed group), and those with a recent/current manic, hypomanic, or mixed episode (non-depressed group) who agreed to enroll directly into the long-term study. Measures of adverse events and safety included treatment-emergent adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Symptom measures included Montgomery Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Results The most common adverse events associated with lurasidone were akathisia (30.7%), nasopharyngitis (26.6%), nausea (12.1%), and somnolence (12.1%). Minimal changes in lipids and measures of glycemic control occurred. Mean change in body weight was + 1.0 kg in the non-depressed group and − 0.8 kg in the depressed group. MADRS total scores declined by a mean (SD) of 2.0 (14.7) points from long-term baseline to endpoint in the depressed group who had received placebo in the prior 6 week trial. The depressed group that had received lurasidone during the prior 6 week study maintained their depressive symptom improvements. For the non-depressed group, YMRS total scores decreased over time. Limitations No control group was included, treatment was open-label, and 49.7% of patients completed the 52 week study. Conclusions Long-term treatment with lurasidone 20–120 mg/day for Japanese patients with bipolar disorder maintained improvements in depressive symptoms for depressed patients who were treated in a prior 6 week trial and led to improvements in manic symptoms among a newly recruited subgroup of patients with a recent/current manic, hypomanic, or mixed episode. Few changes in weight or metabolic parameters were evident. Clinical trial registration: JapicCTI-132319, clinicaltrials.gov—NCT01986114.

AIM The aim of this study was to evaluate the efficacy of lurasidone in acute schizophrenia in Japan and other countries. METHODS Subjects (aged 18-74 years) diagnosed with schizophrenia were randomized to lurasidone 40 mg/day or placebo. The primary efficacy endpoint was change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Secondary efficacy assessments included the Clinical Global Impression-Severity Scale (CGI-S). Safety endpoints included adverse events, and laboratory and electrocardiogram parameters. RESULTS A total of 483 subjects were randomized to lurasidone or placebo; 107 subjects were from Japan. Mean changes from baseline at Week 6 endpoint in PANSS total scores were -19.3 in the lurasidone group and -12.7 in the placebo group (treatment difference: P

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., Using the Bendep‐SRQ‐J, we elucidated the current state of BZ‐RA dependence. Nearly half of the patients were non‐compliant.

The orexinergic system plays a significant role in regulating proper sleep/wake maintenance. Dual orexin receptor antagonist (DORA) is widely prescribed for insomnia symptoms. The antagonist acts on orexin 1 and 2 receptors located in certain brain areas, including the locus coeruleus and dorsal raphe. Nevertheless, its effects on monoamine-related gene expression remain unclear. Here, we measured the expression levels of monoamine-related genes in DORA-treated mice. DORA treatment significantly affected overall levels of noradrenalin transporter/monoamine oxidases A mRNA expression in the hippocampus. Our findings suggest that DORA contributes to noradrenalin-related gene expression regulation in the central nervous system.

Purpose This study was performed to assess the long-term efficacy, safety, and tolerability of brexpiprazole in elderly Japanese patients with schizophrenia. Methods This is a post hoc analysis of a previous open-label study conducted over 56 weeks which consisted of two consecutive phases: a 4-week switching period and a 52-week open-label period. Mean change in the Positive and Negative Syndrome Scale (PANSS) total score, response rates, number and incidence of treatment-emergent adverse events (TEAEs), and other safety parameters were analyzed using descriptive statistics based on age group (elderly, ≥65 and non-elderly, Results This post hoc analysis included 208 de novo patients of which 33 were elderly. The continuation rate in elderly patients was 54.5%, and the mean daily dose and treatment duration of brexpiprazole in elderly patients at week 56 were similar to those of non-elderly patients. The mean change in the PANSS total score from the baseline to week 56 was -13.8 in elderly patients and this improvement was maintained throughout the open-label phase. This outcome was comparable to that of the non-elderly patients (-9.0). The incidence rate of TEAEs was 97.0% in elderly patients and 82.3% in non-elderly patients. Most of the TEAEs were either mild (75.8%) or moderate (18.2%) in severity in the elderly patients and the incidence of TEAEs leading to discontinuation was lower in elderly (9.1%) than in non-elderly patients (13.1%). The most commonly observed adverse events in elderly patients were nasopharyngitis (30.3%) and worsening of schizophrenia (27.3%). The safety profiles in both groups were similar. Conclusion Brexpiprazole was shown to be safe and effective in the treatment of elderly Japanese patients with schizophrenia.

AIM Globally, evidence from short-term studies is insufficient for the guidelines to uniformly recommend a particular antipsychotic(s) for the maintenance treatment of schizophrenia. Therefore, long-term comprehensive evaluation of antipsychotics is required from a social rehabilitation perspective, especially for drugs that have not yet been studied. The Japan Useful Medication Program for Schizophrenia (JUMPs) is a large-scale, long-term naturalistic study to present pivotal 52-week data on the continuity of second-generation antipsychotics (SGA: aripiprazole, blonanserin, and paliperidone). METHODS JUMPs was an open-label, three-arm, randomized, parallel-group, 52-week study. Enrolled patients had schizophrenia, were ≥20 years old, and required antipsychotic treatment or switched from previous therapy. The primary endpoint was treatment discontinuation rate over 52 weeks. Secondary outcomes included remission rate, social functioning, and quality-of-life scores [Personal and Social Performance Scale (PSP) and EuroQol-5 dimensions], and safety. RESULTS In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). The discontinuation rate (P = 0.9771) and remission rates (P > 0.05) over 52 weeks did not differ significantly between the three treatment groups. The discontinuation rates were 68.3%, 68.2%, and 65.5% in the aripiprazole, blonanserin, and paliperidone groups, respectively. Significant improvements (all P

Masaomi Iyo,1 Jun Ishigooka,2 Masatoshi Nakamura,3 Reiko Sakaguchi,4 Keisuke Okamoto,5 Yongcai Mao,6 Joyce Tsai,7 Alison Fitzgerald,8 Kentaro Takai,9 Teruhiko Higuchi10,11 1Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan; 2Institute of CNS Pharmacology, Tokyo, Japan; 3Department of Data Science, Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan; 4Department of Clinical Research, Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan; 5Department of Clinical Operation, Drug Development Division, Sumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan; 6Division of Data Science, Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA; 7Division of Clinical Research, Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA; 8Division of Clinical Operations, Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA; 9Medical Affairs, Sumitomo Dainippon Pharma Co., Ltd., Tokyo, Japan; 10Japan Depression Center, Tokyo, Japan; 11National Center of Neurology and Psychiatry, Tokyo, JapanCorrespondence: Kentaro Takai Email kentaro-takai@ds-pharma.co.jpPurpose: The goal of this study was to evaluate the safety and effectiveness of lurasidone among patients with schizophrenia in a 12-week open-label extension study.Patients and Methods: Patients who completed a 6-week, double-blind, placebo-controlled study were enrolled in a 12-week open-label extension study with flexible dosing of lurasidone at 40 or 80 mg/day. Safety assessments included adverse events, vital signs, laboratory tests, and electrocardiogram (ECG) parameters. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression-Severity Scale (CGI-S), Calgary Depression Scale for Schizophrenia (CDSS) and quality of life measure.Results: A total of 289 patients were enrolled in the open-label extension study. Rates of treatment-emergent adverse events (TEAEs) were low; akathisia was the most common TEAE with an incidence of 6.6%. There were 54 patients (18.7%) who discontinued the extension study, with 17 (5.9%) discontinuing due to adverse events. Minimal or no effects of lurasidone on weight, body mass index, metabolic parameters, prolactin, and ECG parameters were evident. There was continued improvement to week 12 in PANSS and CGI-S scores beyond the initial gains made during the prior 6-week double-blind study. Non-responders to lurasidone 40 mg/day in the prior 6-week study showed a mean (standard deviation) improvement from open-label baseline of 10.7 (13.8) points on the PANSS total score after lurasidone dose was increased to a modal dose of 80 mg/day during the extension study. Changes from double-blind baseline in CDSS and quality of life were maintained in the extension study.Conclusion: Treatment with lurasidone 40 or 80 mg once daily (flexibly dosed) continued to be well tolerated with patients demonstrating further improvement in symptoms over the course of a 12-week open-label extension study in patients with schizophrenia.Keywords: lurasidone, schizophrenia, antipsychotic, safety, effectiveness, open-label

Some psychiatric diseases are associated with disruptions in the circadian clock system. Ziprasidone (ZIP), a second-generation antipsychotic, is widely used for psychiatry-related pharmacotherapy but its mechanism has not been clearly elucidated. We measured clock gene fluctuation patterns in the hippocampus and the amygdala in ZIP-treated mice. ZIP significantly increased Per1, Per2, and Bmal1 mRNA 2 h after the lights were turned off (ZT14) in the hippocampus, but not in the amygdala. These results suggest that ZIP might affect clock gene regulation, which could represent the pathway underlying symptom amelioration.

Clozapine (CLZ), an antipsychotic with a unique mechanism of action, is known to be superior to any other antipsychotic for schizophrenia. However, CLZ is also known to be associated with the development of lethal side effects, which include agranulocytosis and glucose intolerance (GI). Regular measurement and registration of blood test results have been mandatory for all CLZ users; however, these risks may still prevent therapists from prescribing CLZ. While CLZ-induced agranulocytosis has been well documented, CLZ-induced GI in the real world has not been fully investigated. Therefore, in this study, we used data registered in monitoring systems to investigate background factors associated with new-onset GI after CLZ administration and changes in HbA1c levels during CLZ treatment. Data of all patients with schizophrenia who were using CLZ from July 29, 2009 to January 20, 2016 were used for the analysis. Of the 3,746 patients enrolled in the study, 92 (2.5%) had GI at baseline; of the remaining 3,654 patients, 428 (11.7%) developed new-onset GI. Multivariate logistic regression analysis revealed that the development of new-onset GI was significantly associated with older age, higher baseline HbA1c levels, and longer treatment duration. In patients with GI at baseline, HbA1c levels were maintained or improved over 18 months, while in the other patients, CLZ administration gradually elevated HbA1c levels. The findings of this study suggest that, although adequate monitoring and intervention is required, CLZ induction and maintenance therapy may be safe, even for patients with impaired glucose tolerance.

Highlights • The reproduction number had three peaks that came several days before the surge in COVID-19 cases. • There was a strong negative correlation between the kinematic viscosity of atmospheric air and the reproduction number. • One influencing factor is air temperature, which means the winter season could have an effect on viral transmission., Background The large number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has plunged the world into fear in recent times. In Japan, 18,769 novel coronavirus disease 2019 (COVID-19) cases have been reported as of June 30, 2020. This study aimed to assess whether cluster infection prevention is possible by evaluating the association between viral transmission and meteorological factors. Methods This study included 1263 people who were successively diagnosed with COVID-19 in Hokkaido, Japan between January 24, 2020 and June 30, 2020. After obtaining the values from the Japanese Meteorological Agency, the average scores of air temperature and humidity were calculated and compared with COVID-19 reproduction numbers, and the association between COVID-19 incidence or reproduction number and meteorological factors was assessed. Results The COVID-19 reproduction number in Hokkaido had three peaks that came several days before the surge in COVID-19 cases. The peaks are indicative of cluster infections. There was a strong negative correlation between the kinematic viscosity of atmospheric air and the reproduction number. Discussion and Conclusion Analysis of the reproduction number is important for predicting or suppressing COVID-19 infection clusters. The authors found a strong association between meteorological factors, such as kinematic viscosity of atmospheric air and the incidence of COVID-19 infection. Meteorological forecasts could provide foreknowledge about COVID-19 infection clusters in the future.

Background Blonanserin transdermal patch therapy is now available in Japan for the treatment of schizophrenia and may provide several advantages over the tablet formulation. Objective The aim was to evaluate the long-term safety and efficacy of blonanserin transdermal patches in Japanese patients with schizophrenia. Methods An open-label study was conducted in adults with schizophrenia at 37 sites in Japan. Patients were enrolled in either cohort 1 or 2. Patients in cohort 1 received 8–16 mg/day blonanserin tablets for 6 weeks and then 40–80 mg/day blonanserin patches for 52 weeks. The dose of blonanserin patches was determined according to the dose of the tablets. In cohort 2, every patient started from 40 mg/day and then 40–80 mg/day blonanserin transdermal patches for 52 weeks. Both cohorts had 1–2 weeks of follow-up. Safety endpoints included the incidence of adverse events (AEs), treatment-related AEs, extrapyramidal AEs [also assessed using the change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score], the use of any concomitant antiparkinsonian drugs, and skin-related AEs, including skin irritation. Patients also underwent assessment of laboratory values including for serum prolactin concentration, vital signs, body weight, electrocardiographic (ECG) changes, and the corrected QT (QTc) interval. Suicidal ideation was assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS) score. Efficacy was assessed via duration of blonanserin transdermal patch treatment, Positive and Negative Syndrome Scale (PANSS) total and subscale scores, and Clinical Global Impression-Severity (CGI-S) scores. Other endpoints included total Drug Attitude Inventory 10 (DAI-10) scores, EuroQol-5 Dimension (EQ-5D) effect values, and a patient questionnaire about the dosage form. Results A total of 223 patients with consents, 117 in cohort 1 and 106 in cohort 2 were included in the study. Of the 117 patients in cohort 1, 108 were treated with blonanserin tablets, and 97 received blonanserin patches and were included in the safety analysis set. In cohort 2, 103 of the 106 patients were treated with blonanserin transdermal patches and were included in the safety analysis set. In total, 91 patients were male (45.5%). The mean age was 43.8 years. Discontinuation occurred in 40 patients (41.2%) in cohort 1 and 44 patients (42.7%) in cohort 2. Discontinuation resulted from AEs in 18.6% (cohort 1) and 11.7% (cohort 2) and from withdrawal of consent in 13.4% (cohort 1) and 20.4% (cohort 2), and seven patients overall discontinued due to skin reactions. AEs were reported in 174 patients (87.0%), and 13 serious AEs occurred in 12 patients (6.0%), of which six patients were in cohort 1 and six patients were in cohort 2. Serious AEs were six schizophrenia (n = 6) and seven other AEs (n = 6), which included impulse-control disorder, fracture, epistaxis, asthma, pneumonia aspiration, pneumonia hemophilus, and pneumonia. The most common AEs were nasopharyngitis (n = 62, 31.0%), application site erythema (n = 45, 22.5%), application site pruritus (n = 23, 11.5%), and akathisia (n = 20, 10.0%). AE incidence was similar in cohort 1 (84.5%) and cohort 2 (89.3%). Extrapyramidal and skin-related AEs were reported in 51 patients (25.5%) and 83 patients (41.5%), respectively. None of these AEs were serious. The mean change from baseline in total DIEPSS score at Week 52 {last observation carried forward [LOCF] (standard deviation [SD])} was −0.1 (1.55), indicating no marked effect. In terms of concomitant medications used in cohort 1 and cohort 2, 33.0% (32/97) and 22.3% (23/103) used antiparkinsonian drugs, respectively. The majority of skin-related AEs occurred early in treatment and were appropriately managed with topical therapies. Of the patients who answered “No” to all C-SSRS categories at baseline (n = 129), 13 patients (10.1%) were evaluated as having emergence of suicidal ideation. Among patients who answered “No” to all C-SSRS suicidal behavior categories at baseline (n = 172), one (0.6%) was evaluated as having suicidal behavior during blonanserin transdermal patch treatment. There were no clinically significant changes in laboratory tests or examinations, including prolactin level, vital signs, body weight, ECG, metabolism-related parameters, and QTc interval. The mean (SD) change in body weight was − 0.04 (4.561) kg and − 0.67 (6.841) kg in cohort 1 and cohort 2, respectively. The mean changes from baseline in PANSS total score at Week 52 (LOCF [SD]) were − 0.1 [11.6] and − 3.4 [15.3] in cohort 1 and 2, respectively. PANSS scores did not change after switching from tablet to patch formulation in cohort 1 and decreased over the 52 weeks of treatment with the blonanserin patches. The mean change from baseline in CGI-S score at Week 52 (LOCF [SD]) was − 0.2 [1.03] in both cohorts combined. After 52 weeks of blonanserin patch treatment, the total DAI-10 score increased or remained unchanged compared with baseline in 82 of the 129 patients (63.6%) for whom these data were available. In the intention-to-treat population of the combined cohorts (n = 200), the mean (SD) change from baseline in EQ-5D score at the last assessment was − 0.0365 (0.17603). Patients’ attitudes to the blonanserin transdermal patches were generally positive. Conclusions Blonanserin transdermal patches are safe and effective in the long-term treatment of schizophrenia. ClinicalTrials.gov registration NCT02335658. Electronic supplementary material The online version of this article (10.1007/s40263-019-00692-6) contains supplementary material, which is available to authorized users.

Objectives To determine the long‐term safety of switching to brexpiprazole from aripiprazole or non‐aripiprazole dopamine antagonists. Methods Post‐hoc analysis of 56‐week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4‐week switching period with further titration (1–4 mg/day) allowed during the 52‐week, open‐label period. Major assessment items: total/low‐density lipoprotein (LDL)‐/high‐density lipoprotein (HDL)‐cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc). Results 84/186 (45.2%) patients (aripiprazole, 32.9%; non‐aripiprazole, 54.8%) discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL‐/HDL‐cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight (aripiprazole, 1.1 [4.4] kg; non‐aripiprazole, 0.4 [4.6] kg). Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non‐aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients (aripiprazole, 84.1% [serious, 9.8%]; non‐aripiprazole, 88.5% [serious, 14.4%]). Few changes occurred in extrapyramidal symptom scales or QTc interval. Conclusions Switching to brexpiprazole is associated with a low long‐term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms.

Background Lurasidone has demonstrated efficacy for short-term treatment of bipolar depression in a diverse ethnic population including Japanese. This study evaluated the long-term safety and effectiveness of open-label lurasidone treatment in these patients. Methods Patients for this 28-week extension study were recruited from those who completed a 6-week double-blind study of lurasidone, 20-60 mg/day, lurasidone 80-120 mg/day, and placebo. In the extension study, lurasidone was flexibly dosed (20 to 120 mg/day). Safety was evaluated in terms of change from extension-phase baseline to endpoint including adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Effectiveness was determined by Montgomery Asberg Depression Rating Scale (MADRS) and other measures. Results 303 of 413 (73.3%) subjects completed the extension study. Discontinuation due to a treatment-emergent adverse event occurred for 11.4% of those who received placebo, and 8.9% of those who received lurasidone, in the prior 6-week trial. The most common treatment-emergent adverse event was akathisia. Minimal changes were evident on body weight and metabolic parameters. Long-term treatment with lurasidone further reduced mean MADRS total scores from long-term baseline to week 28 (or endpoint) for both those who had received prior placebo (-11.3), and those who had receive prior lurasidone (-8.9), in the 6-week double-blind trial. Limitations There was no placebo control and treatment was not double-blind. Conclusions Long-term treatment with lurasidone (20-120 mg/day) was well-tolerated with no new safety concerns and associated with continued improvement in depressive symptoms in this international sample of patients with bipolar depression. Clinical trial registration JapicCTI-132319, clinicaltrials.gov - NCT01986114

Aim Previous studies conducted primarily in the USA and Europe have demonstrated the efficacy and safety of lurasidone 20-120 mg/day for the treatment of bipolar I depression. The aim of the current study was to evaluate the efficacy and safety of lurasidone monotherapy for the treatment of bipolar I depression among patients from diverse ethnic backgrounds, including those from Japan. Methods Patients were randomly assigned to double-blind treatment for 6 weeks with lurasidone, 20-60 mg/day (n = 184) or 80-120 mg/day (n = 169), or placebo (n = 172). The primary end-point was change from baseline to Week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS). Results Lurasidone treatment significantly reduced mean MADRS total scores from baseline to Week 6 for the 20-60-mg/day group (-13.6; adjusted P = 0.007; effect size = 0.33), but not for the 80-120-mg/day group (-12.6; adjusted P = 0.057; effect size = 0.22) compared with placebo (-10.6). Treatment with lurasidone 20-60 mg/day also improved MADRS response rates, functional impairment, and anxiety symptoms. The most common adverse events associated with lurasidone were akathisia and nausea. Lurasidone treatments were associated with minimal changes in weight, lipids, and measures of glycemic control. Conclusion Monotherapy with once daily doses of lurasidone 20-60 mg, but not 80-120 mg, significantly reduced depressive symptoms and improved functioning in patients with bipolar I depression. Results overall were consistent with previous studies, suggesting that lurasidone 20-60 mg/day is effective and safe in diverse ethnic populations, including Japanese.

Purpose This study was performed to assess the long-term efficacy, safety, and tolerability of brexpiprazole in elderly Japanese patients with schizophrenia. Methods This is a post hoc analysis of a previous open-label study conducted over 56 weeks which consisted of two consecutive phases: a 4-week switching period and a 52-week open-label period. Mean change in the Positive and Negative Syndrome Scale (PANSS) total score, response rates, number and incidence of treatment-emergent adverse events (TEAEs), and other safety parameters were analyzed using descriptive statistics based on age group (elderly, ≥65 and non-elderly

Background To date, no previous studies have evaluated the relationship between sleep duration and quality of life (QOL) or depression in the general population after controlling for daytime sleepiness and sleep disturbances. Methods A web-based cross-sectional survey was conducted with 8698 subjects aged 20–69 years. We examined the relationships between weekday sleep duration and daytime sleepiness, sleep disturbance, QOL and depression, using the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (without the item for sleep duration), 8-item Short Form and Center for Epidemiological Studies Depression Scale (CES-D). Results Daytime sleepiness tended to increase in proportion to shorter weekday sleep durations. Sleep disturbances, physical and mental QOL, and CES-D scores were worse in both the shorter and longer sleep groups compared with the group with 7–8 h of sleep. Hierarchical logistic regression analyses revealed that short sleep duration but not long sleep duration was significantly associated with reduction of both physical and mental QOL, even after controlling for the presence of daytime sleepiness and sleep disturbance. Both short and long sleep duration were independently and significantly correlated with depression after controlling for daytime sleepiness; however, there was no statistically significant association after adjusting for the effects of sleep disturbance. Conclusions The results suggested adverse effects of short sleep but not long sleep on both physical and mental QOL. In addition, the negative impact of specific types of sleep disturbance on depression may be greater than the impact of shortening of sleep duration.

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using three independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all three cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.

OBJECTIVE To determine the prevalence, background factors, and progression of and recovery from clozapine-induced agranulocytosis in Japan. METHODS Data on treatment-resistant schizophrenia patients registered with the Clozaril Patient Monitoring Service (CPMS) between July 29, 2009 and January 20, 2016 were extracted. Patients with a neutrophil count

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Objective The aim of this study was to investigate clozapine use and its associated adverse effects in patients in Japan. Methods We analyzed data recorded from July 2009 to January 2016 (N = 3780 patients) in the Clozaril Patient Monitoring Service, which was established in Japan in 2009 and includes all Japanese patients who have been prescribed clozapine. Results The treatment discontinuation rate was 23.9% (869/3780 cases). The average ± SD treatment duration was 234.9 ± 306.9 days (median, 115 days), and the average ± SD dosage was 186.41 ± 151.6 mg/d. The estimated treatment continuation rates resulting from all-cause discontinuation were 78.2 after 1 year and 72.9% after 2 years of treatment. The incidence of neutropenia/leucopenia was 5.4% (206/3780 cases). The average ± SD dose before discontinuation was 233.36 ± 168.15 mg (median, 200 mg; range, 4-600 mg). The incidence of glucose intolerance was 15.4% (583/3780 cases). Of 3780 patients, 98 (2.67%) developed glucose intolerance before and after taking clozapine administration, whereas 485 patients (12.8%) developed glucose intolerance after taking clozapine. The average ± SD time from treatment initiation to new onset of glucose intolerance was 382.2 ± 420.2 days (median, 216 days; range, 4-2053 days). Conclusions The data obtained in this study, particularly regarding the incidence of clozapine-induced adverse events, will enable the optimal and safe use of clozapine in Japanese patients with treatment-resistant schizophrenia.

Although the benzodiazepine class of drugs has proven useful in treating anxiety symptoms, recent studies yield no consistent empirical support for their use in treating psychiatric disorders. However, animal studies using a fear conditioning paradigm have suggested that benzodiazepines facilitate fear memory extinction, dependent on treatment timing and subject conditions. However, we have no data on the effect of subject conditions. The purpose of this study was to investigate whether the effect of benzodiazepines depends on hypersensitivity to fear-memory processing. We examined the effect of diazepam, a benzodiazepine, on the extracellular dopamine level in the left amygdala of methamphetamine-sensitized, fear-conditioned model rats, using microdialysis and high-performance liquid chromatography. In this model, the dopamine level in the amygdala excessively increases in response to a fear-conditioned stimulus; the phenomenon has been proposed as a biological marker for hypersensitivity to fear-memory processing. Diazepam inhibited this excessive increase. The extent of the inhibitory effect was greater in the sensitized condition. Diazepam alone increased amygdalar dopamine levels under physiological conditions but not under sensitized conditions. Diazepam did not shorten freezing time in any group. These results suggest that diazepam modulates amygdala dopamine with state dependence and that amygdalar dopamine fine-tuning accounts for part of the therapeutic effect of benzodiazepines on fear memory processing. Further investigation is required to identify patients suitable for treatment with benzodiazepines. This is the first report on the pharmacodynamic effects of benzodiazepine on the amygdalar dopamine basal level and on fear memory processing.

Aim This study aimed to evaluate the efficacy, safety, and tolerability of brexpiprazole compared to placebo in Japanese patients with acute schizophrenia (SCZ). Methods We conducted a 6-week, multicenter, double-blind, placebo-controlled, phase 2/3 study in Japan. Patients with acute SCZ were randomized (1:1:1:1) to receive brexpiprazole 1 mg, 2 mg, 4 mg, or placebo once a day. The primary endpoint was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total scores. Results In the 459 patients that were randomized, brexpiprazole 2 mg showed a significant improvement versus placebo (treatment difference: -7.32, P = 0.0124), although brexpiprazole 4 mg showed numerical improvements (treatment difference: -3.86, P = 0.1959), and brexpiprazole 1 mg showed only minimal change (treatment difference: -0.63, P = 0.8330). Treatment-emergent adverse events with an incidence of ≥5% and ≥2 times the rate of placebo in the brexpiprazole groups were vomiting, elevated blood prolactin, diarrhea, nausea, and dental caries. Most treatment-emergent adverse events were mild or moderate in severity. There were no clinically significant changes in electrocardiogram parameters, bodyweight, laboratory values, or vital signs in the brexpiprazole groups. Conclusion Brexpiprazole was efficacious and well tolerated in Japanese adult patients with acute SCZ.

Aim The purpose of this study was to evaluate the safety and efficacy of aripiprazole in adolescents with schizophrenia (SCZ) in Japan. Methods In a 6-week, randomized, double-blind, dose-comparison study, adolescents (aged 13-17 years) with SCZ were randomized to receive aripiprazole 2, 6-12, or 24-30 mg/day. Patients who completed the 6-week study participated in a 52-week, flexible-dose, open-label extension (OLE) study of aripiprazole (initial dose: 2 mg/day, maintenance dose: 6-24 mg/day, maximum dose: 30 mg/day). Results In the 6-week study, the percentage of patients completing treatment was: 77.1% (27/35) for 2 mg/day; 80.0% (24/30) for 6-12 mg/day; and 85.4% (35/41) for 24-30 mg/day. The least squares mean change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to endpoint (primary efficacy endpoint, last observation carried forward) was -19.6 for 2 mg/day, -16.5 for 6-12 mg/day, and - 21.6 for 24-30 mg/day. The most common (≥20% patients in any group) treatment-emergent adverse events (TEAE) were nausea, akathisia, insomnia, and somnolence. Most TEAE were mild or moderate in severity. There were no deaths. In the OLE, 60.3% (41/68) of patients completed treatment, and the PANSS total score decreased by -7.9 from OLE baseline to week 52. The most common (≥20% patients) TEAE were nasopharyngitis and somnolence. Most TEAE were mild or moderate in severity. There were no deaths. Conclusion These study results suggest that aripiprazole would be safe and well tolerated in both short- and long-term treatment for adolescents with SCZ in Japan.

For prevention and early detection of dependence on hypnotics such as benzodiazepines (BZDs) or its agonists, a withdrawal symptom scale specialized for this kind of drug has long been sought. In this study, the benzodiazepine hypnotics withdrawal symptom scale (BHWSS) was developed using item response theory (IRT). This study enrolled 121 chronic insomnia patients (mean age 46.1 ± 15.6 years) who had been treated with hypnotics for 3 or more months. The patients were asked to fill a questionnaire that was developed by selecting questions from Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) and Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) on the basis of the symptoms triggered by reduction or abrupt cessation of the intake of hypnotics. A factor analysis was performed to verify the assumption that the new scale had one dimension. We drew item response category characteristic curves, following the IRT. Besides statistical considerations, clinical implications were also incorporated to select the 12 items used to construct the BHWSS questionnaire. Using the analyses based on IRT, 6 items each were selected from BWSQ and CIWA-B. The cumulative proportion of contribution of the first factor, obtained by factor analysis, was found to be 0.36. Cronbach’s α coefficient and McDonald’s ω coefficient were calculated to be 0.86 and 0.87, respectively. The total score of 12 items increased monotonically with the increasing level of withdrawal symptoms. The BHWSS could potentially become a practical tool for estimating the degree of BZD withdrawal symptoms.

Objective Obstructive sleep apnea syndrome (OSAS) and insufficient sleep might increase the risk of drowsy driving and sleepiness-related vehicular accidents. This study retrospectively investigated the factors associated with these driving problems, particularly addressing OSAS severity and sleep amounts of affected drivers. Methods This study examined 161 patients (146 male and 15 female) with OSAS (apnea−hypopnea index [AHI] ≥ 5) who drove on a routine basis and who completed study questionnaires. To investigate factors associated with drowsy driving during the prior year and sleepiness-related vehicular accidents or near-miss events during the prior five years, logistic regression analyses were performed with age, body mass index, monthly driving distance, habitual sleep duration on weekdays, the Japanese version of Epworth Sleepiness Scale score, AHI, and periodic limb movement index as independent variables. Results Of the patients, 68 (42.2%) reported drowsy driving experiences, and 86 (53.4%) reported sleepiness-related vehicular accidents or near-miss events. Analyses revealed the following: older age (46–65 years, ≥66 years) was negatively associated with drowsy driving ( p 0.05, p 0.05), and habitually shorter sleep duration on weekdays (≤6 hours) was positively associated with drowsy driving ( p 0.01). Habitual sleep duration of ≤6 hours ( p 0.01) and Epworth Sleepiness Scale score of ≥11 ( p 0.01) were positively associated with sleepiness-related vehicular accidents and near-miss events. However, AHI was not associated with these driving problems. Conclusion Insufficient sleep, rather than severity of OSAS, was associated with sleepiness-related driving problems in these Japanese OSAS patients.

A post hoc analysis was performed using data obtained over eight weeks from 200 Japanese patients with schizophrenia who were switched to brexpiprazole monotherapy in a long‐term treatment study. The 8‐week period comprised of a 4‐week switching phase and a 4‐week post‐switch phase. For the antipsychotic switching schedule, brexpiprazole was first administered at 1 mg/day and increased to 2 mg/day by the end of week 4. Concurrently, the previous antipsychotic(s) was/were tapered gradually from the start of week 3 and discontinued by the end of week 4. Brexpiprazole could then be increased up to 4 mg/day according to the CGI‐I criteria. At week 8, 1.8%, 23.2%, 25.0%, and 50% of patients were administered daily brexpiprazole doses of 1, 2, 3, and 4 mg, respectively. The discontinuation rate at week 8 was 17.0%. The major reasons for discontinuation were consent withdrawal (9.5%), occurrence of adverse events (5.5%), and physician's decision (2.0%). Commonly reported adverse events were nasopharyngitis (13.5%), schizophrenia (9.0%), insomnia (6.5%), headache (5.5%), and akathisia (5.5%). The discontinuation rate was 4.9% for patients who were switched from aripiprazole as the primary antipsychotic and 25.4% for those who were switched from other antipsychotics. Owing to the serious adverse events that led to treatment discontinuation, careful switching to brexpiprazole is necessary in patients who previously used olanzapine as their primary antipsychotic., A post hoc analysis was performed using data obtained over eight weeks from 200 Japanese patients with schizophrenia who were switched to brexpiprazole monotherapy in a long‐term treatment study. The 8‐week period comprised of a 4‐week switching phase and a 4‐week post‐switch phase. The discontinuation rate was 4.9% for patients who were switched from aripiprazole as the primary antipsychotic and 25.4% for those who were switched from other antipsychotics.

Objective: Many patients with implantable cardioverter defibrillators experience depressive symptoms. In addition, avoidance behavior is a common problem among patients with implantable cardioverter defibrillators. We examined the association between avoidance behaviors and depressive symptoms in patients with implantable cardioverter defibrillators. Method: We conducted a single-center, cross-sectional study with self-completed questionnaires between May 2010 and March 2011. We measured avoidance behaviors (avoidance of places, avoidance of objects, and avoidance of situations) and depressive symptoms (using the Beck Depression Inventory, Version II) in 119 participants. An avoidance behaviors instrument was developed for this study and we confirmed its internal consistency reliability. Results: Ninety-two (77.3%) patients were aged older than 50 years, and 86 (72.3%) were men. Fifty-one (42.9%) patients reported “avoidance of places”, 34 (28.6%) reported “avoidance of objects”, and 63 (52.9%) reported “avoidance of activity”. Avoidance behavior was associated with increased odds for the presence of depressive symptoms (OR 1.31; 95% CI 1.06–1.62). Conclusions: This was the first study to identify the relationship between avoidance behavior and depressive symptoms among patients with implantable cardioverter defibrillators; however, there are a few methodological limitations.

Background AAT (Animal-assisted therapy) was developed to promote human social and emotional functioning as a day care program for psychiatric patients. Aims In this study, we performed AAT using a pet-type robot, AIBO for schizophrenic patients. Methods After obtaining informed consent, we performed the AIBO-assisted therapy for three schizophrenic (ICD-10, F20.x2) patients (male: 1, female: 2) whose medication did not change over the 8 weeks study period in a ward. Results It was found that the AAT using AIBO may be useful for the patients with negative and general psychopathological symptoms such as “Anxiety” and “Uncooperativeness”. Conclusion We make use of this result, and we want to develop the AAT program using a pet-type robot, AIBO which may be suitable for Japanese psychiatric patients.