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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, multicenter, open-label extension study enrolled adolescent patients with schizophrenia who opted to enter in this study after the completion of the preceding placebo-controlled study. Blonanserin tablet was orally administered twice daily, after morning and evening meals, for 52 weeks using dose-titration method within a range between 4 and 24 mg/day. The primary end point was the change from baseline to the end of the study in the Positive and Negative Syndrome Scale (PANSS) total score. Safety/tolerability was assessed by the incidence and severity of adverse events. Results: Of 117 patients who completed the preceding placebo-controlled study, 109 entered this extension study and 43 (39.4%) of them discontinued the study treatment. The safety analysis set comprised 106 patients who received the study drug at least once, including 36 and 70 patients treated with placebo (DB-placebo group) and blonanserin tablet (DB-blonanserin group), respectively, in the placebo-controlled study. At the last assessment, the mean change in PANSS total score overall [mean (standard deviation)] was -24.9 (20.76) from the baseline of the placebo-controlled study, which was similar in the DB-placebo and DB-blonanserin groups. The overall incidence of adverse events was 90.6%, and most of them were mild or moderate in severity, with similar incidence of extrapyramidal symptoms (38.7%) to that in adults receiving long-term blonanserin oral tablet treatment and minimal change in weight and metabolic parameters. Conclusions: This long-term extension study showed that 52 weeks of oral blonanserin treatment improved or stabilized psychiatric symptoms in patients with adolescent schizophrenia. There were no major issues with the safety or tolerability of blonanserin administration in this study. Considering relatively less adverse effects on weight increase and metabolic parameters, blonanserin is expected to be a safe/tolerable treatment option for adolescent schizophrenia that can be used seamlessly from adolescence to adulthood.

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 < 0.05) from baseline in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favored blonanserin., Conclusion: All three SGAs evaluated in this study showed similar treatment discontinuation rates in patients with chronic schizophrenia in Japan., (© 2021 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

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., (© 2021. The Author(s).)

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., (© 2021 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.)

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 < 0.001, effect size = 0.41). Changes from baseline for Week 6 CGI-S scores were -1.0 for lurasidone and -0.7 for placebo (treatment difference: P < 0.001, effect size = 0.41). All-cause discontinuation during the 6-week, double-blind period was 19.4% for lurasidone and 25.4% for placebo, and discontinuation rates due to adverse event were 5.7% for lurasidone and 6.4% for placebo. The following common treatment-emergent adverse events occurred in more than 2% on lurasidone and at a rate at least twice that of the placebo group: akathisia (4.0%), dizziness (2.8%), somnolence (2.8%), abdominal discomfort (2.0%) and asthenia (2.0%). No significant changes in bodyweight or metabolic parameters were observed., Conclusion: Lurasidone 40 mg once daily dosing demonstrated efficacy in a patient population with acute schizophrenia, including subjects from Japan, and was generally safe and well-tolerated., (© 2021 Sumitomo Dainippon Pharma Co., Ltd Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

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., (© 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of NeuropsychoPharmacology.)

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 Åsberg 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., (Copyright © 2020. Published by Elsevier B.V.)

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., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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-Åsberg 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., (© 2020 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

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 3 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 3 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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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., Competing Interests: Declaration of Competing Interest The authors indicate no potential conflicts of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

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 <500/mm 3 were defined as having agranulocytosis, and those with a leukocyte count <3,000/mm 3 or a neutrophil count <1,500/mm 3 but not meeting the criteria for agranulocytosis were defined as having leukopenia/neutropenia., Results: Of 3,746 patients, agranulocytosis and leukopenia/neutropenia were observed in 38 (1.0%) and 182 (4.9%) patients, respectively. Age was significantly higher in the agranulocytosis group (p < .001). Decreased leukocyte counts 1 week prior to discontinuation were observed only in the agranulocytosis group. The median number of days to recovery from agranulocytosis and leukopenia/neutropenia was 10 and 4, respectively, with more variation in the latter., Conclusions: Although some patients with leukopenia/neutropenia might carry less pathologic significance, the results of this study reconfirmed the importance of regular blood monitoring for preventing agranulocytosis., (© 2020 John Wiley & Sons Ltd.)

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., (© 2020. Otsuka Pharmaceutical Co Ltd. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Introduction: This study was designed to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia among Asian patients., Methods: Patients (N = 281) with schizophrenia who had completed a randomized, double-blind (DB), 6-week comparison of lurasidone (40 and 80 mg/day) and placebo were enrolled in a 26-week extension study in which all patients received open-label (OL), flexible doses of lurasidone (40 or 80 mg/day). Effectiveness was measured using the Positive and Negative Syndrome Scale (PANSS) scale., Results: Fifty-seven percent of patients completed the OL extension study; 16.7% discontinued early due to lack of effectiveness; and 10.3% due to adverse events. The most common adverse events were insomnia (11.3%), akathisia (11.0%), and nasopharyngitis (10.6%). Adverse events related to weight gain, metabolic parameters, prolactin, and ECG measures were uncommon. Mean change in the PANSS total score from the DB baseline to OL endpoint was -28.4, with mean improvement of -7.5 observed from baseline to OL endpoint, and with a PANSS responder rate of 73.7%., Discussion: The results of the current 26-week extension study found lurasidone to be a generally safe, well-tolerated, and effective long-term treatment for schizophrenia in Asian patients., (© 2019 John Wiley & Sons Australia, Ltd.)

Background: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia. This study determined the efficacy, safety and pharmacokinetics of a blonanserin transdermal patch in patients with acutely exacerbated schizophrenia., Methods: This double-blind, multicenter, phase 3 study consisted of a 1-week observation period during which patients were treated with two patches of placebo, followed by a 6-week double-blind period where patients were randomized (1:1:1) to receive once-daily blonanserin 40 mg, blonanserin 80 mg, or placebo patches. The primary endpoint was the change from baseline in the total Positive and Negative Symptom Scale (PANSS) score. Safety assessments included treatment-emergent adverse events (TEAEs)., Results: Between December 2014 and October 2018, patients were recruited and randomly assigned to blonanserin 40 mg (n = 196), blonanserin 80 mg (n = 194), or placebo (n = 190); of these, 77.2% completed the study. Compared with placebo, blonanserin significantly improved PANSS total scores at 6 weeks (least square mean [LSM] difference vs placebo: -5.6 with blonanserin 40 mg; 95% confidence interval [CI] -9.6, -1.6; adjusted p = 0.007, and - 10.4 with blonanserin 80 mg; 95% CI -14.4, -6.4; adjusted p < 0.001). Blonanserin was well tolerated; the most common TEAEs reported were application-site erythema and pruritus, akathisia, tremor, and insomnia., Conclusions: Blonanserin transdermal patch improved the symptoms of acute schizophrenia with acceptable tolerability., Competing Interests: Declaration of Competing Interest NI reports personal fees from Otsuka, Sumitomo Dainippon, Janssen, Eli Lilly, and Pfizer, grants from Otsuka, Daiichi-Sankyo, outside the submitted work. JI reports grants from Sumitomo Dainippon during the conduct of the study, personal fees from Meiji Seika Pharma, MSD, Astellas, Novartis, Pfizer, Otsuka, Eli Lilly, Takeda, and Eisai, outside the submitted work. WHK reports grants from Sumitomo Dainippon, during the conduct of the study. TH reports personal fees from Meiji Seika Pharma, MSD, Allergan, Eisai, Pfizer, Janssen, Lundbeck, Shionogi, Yoshitomi, Kyowa Hakko Kirin, Mochida, Otsuka, Sumitomo Dainippon, Mitsubishi Tanabe, Eli Lilly, and Takeda, outside the submitted work. CUC reports personal fees from Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, Bristol-Myers Squibb, and UpToDate, grants from Janssen and Takeda, other from Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, Teva, and LB Pharma, outside the submitted work. JMK reports personal fees from Alkermes, Sumitomo Dainippon, Eli Lilly, EnVivo Pharmaceuticals (Forum), Forest (Allergan), Genentech, H. Lundbeck, Intracellular Therapies, Janssen, Johnson and Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda and Teva, grants from Otsuka, Lundbeck and Janssen, participated in advisory boards for Alkermes, Sumitomo Dainippon, Intracellular Therapies, Lundbeck, Neurocrine, Otsuka, Pierre Fabre, Takeda and Teva, outside the submitted work. JMK is a shareholder in Vanguard Research Group and LB Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Study Objectives: The herbal medicine Yokukansan (YKS; Yi-Gan San in Chinese) is reported to be effective for treating rapid eye movement sleep behavior disorder (RBD). However, the effectiveness and safety of YKS treatment have not been confirmed in a large sample. Thus, we retrospectively analyzed the outcomes of YKS treatment on patients with RBD using clinical records., Methods: Treatment outcomes were evaluated using the Clinical Global Impression of Illness Severity (CGI-S) and Improvement (CGI-I) scales. Patients with scores of 1 (very much improved) and 2 (much improved) on the CGI-I were classified as responders. After excluding patients with very mild RBD symptoms and those without detailed clinical information, 36 patients with idiopathic RBD including 17 receiving YKS monotherapy and 19 receiving YKS add-on therapy in addition to other medication were analyzed., Results: The patients' mean age [standard deviation, SD] was 69.3 [6.8] years, and the mean duration of RBD morbidity [SD] was 5.7 [3.5] years at the start of YKS treatment. Importantly, 12 of 17 patients (70.6%) receiving YKS monotherapy were responders. However, among patients receiving YKS add-on therapy, the proportion of responders was substantially lower (4 of 19 patients; 21.1%). No adverse events were reported, other than mild gastric distress in one case., Conclusions: Considering the effectiveness of YKS and the low likelihood of adverse events, YKS should be considered as a potential treatment for patients with RBD., Citation: Matsui K, Sasai-Sakuma T, Ishigooka J, Nishimura K, Inoue Y. Effect of yokukansan for the treatment of idiopathic rapid eye movement sleep behavior disorder: a retrospective analysis of consecutive patients. J Clin Sleep Med. 2019;15(8):1173-1178., (© 2019 American Academy of Sleep Medicine.)

Introduction: To evaluate efficacy and safety of lurasidone for the treatment of Asian patients with schizophrenia., Methods: Patients with schizophrenia from Japan, South Korea, Malaysia, and Taiwan were randomly assigned to 6 weeks of double-blind treatment with 40 or 80 mg/d of lurasidone or placebo. The primary efficacy measure was change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total score. Efficacy was evaluated using a mixed-model repeated-measures (MMRM) analysis in the modified intention-to-treat (mITT) population., Results: On the basis of the analysis for the mITT population, the estimated difference score for lurasidone 40 and 80 mg/d vs placebo was -4.8 (P = 0.050) and -4.2 (P = 0.080). For the full intention-to-treat (ITT) population, the difference score for lurasidone 40 and 80 mg/d vs placebo was -5.8 (P = 0.017) and -4.2 (P = 0.043). The most frequent adverse events in the lurasidone 40 and 80 mg/d and placebo groups, respectively, were akathisia (7.3%, 10.4%, 3.3%), somnolence (6.0%, 2.6%, 0.7%), and vomiting (6.0%, 5.8%, 2.0%). The proportion of patients experiencing clinically significant weight gain (≥7%) was 5.3% for lurasidone 40 mg/d, 1.3% for 80 mg/d, and 1.4% for placebo. End point changes in metabolic parameters and prolactin were comparable for both lurasidone groups and placebo., Conclusions: In the ITT (but not the mITT) population, treatment with lurasidone was associated with significant improvement in the PANSS total score in patients with schizophrenia. Lurasidone was generally well tolerated with minimal impact on weight and metabolic parameters., (© 2019 John Wiley & Sons Australia, Ltd.)

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.

Serotonin reuptake inhibitors modulate the serotonergic pathways of the nervous system and are widely used for treating psychiatric conditions such as anxiety and depression. The dopaminergic system is related to the development of these conditions. Previous studies on methamphetamine-sensitised rats (behavioural models of stress vulnerability) have shown increased release of dopamine in response to conditioned stress in the amygdala. This biochemical abnormality was proposed to underlie the pathophysiology of stress vulnerability. However, the effect of serotonin reuptake inhibitors on dopamine levels and its consequent impact on emotional processing is unclear. Here we examined the acute effect of escitalopram, a highly selective serotonin reuptake inhibitor, on fear-related behaviour, baseline dopamine release and dopamine release in response to conditioned fear stress in the amygdala of model rats. Male Sprague-Dawley rats received 2 mg/kg/day, s.c. of methamphetamine for 10 days to sensitise them to the drug, and a fear conditioning paradigm was instituted to model psychological stress. Dopamine changes in the amygdala in response to systemic administration of escitalopram followed by conditioned fear stress were measured using microdialysis and high-performance liquid chromatography. Baseline dopamine release in the amygdala was increased by escitalopram in non-sensitised rats but not in methamphetamine-sensitised rats. Escitalopram attenuated dopamine release in response to the fear-conditioned stimulus in both sensitised and non-sensitised rats. The extent of suppression in methamphetamine-sensitised rats (- 90%) was greater than that in non-sensitised rats (- 48%). These findings suggest that serotonin reuptake inhibitors indirectly stabilise the dopaminergic pathway and modulate emotional processing in the amygdala., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

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., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.

Aim: This study assessed the long-term safety, tolerability, and maintenance of the therapeutic effect of brexpiprazole in Japanese patients with schizophrenia., Methods: This 52-week, open-label, flexible-dose (1-4 mg/day) study included patients with schizophrenia who continued treatment from a short-term randomized placebo-controlled fixed-dose (1, 2, or 4 mg/day) trial and de novo patients who switched from other antipsychotics., Results: A total of 282 patients (184 de novo and 98 rolled over from short-term trial) entered the 52-week treatment with brexpiprazole, and 150 (53.2%) patients completed the week-52 assessment. Treatment-emergent adverse events (TEAE) were experienced by 235/281 patients (83.6%), and TEAE reported by ≥10% of all patients were nasopharyngitis (23.1%) and worsening of schizophrenia (22.4%). During the study, most of the TEAE were mild or moderate in severity, and there were no deaths, and no clinically meaningful mean changes in laboratory values, vital signs, or electrocardiogram parameters. Mean scores for the Positive and Negative Syndrome Scale total and Clinical Global Impression-Severity remained stable until week 52., Conclusion: Brexpiprazole was generally safe and well tolerated and maintained therapeutic effects in the long-term treatment of Japanese patients with schizophrenia., (© 2018 The Authors. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.)

Background: Although a score of less than 7 for the 17-item Hamilton Depression Rating Scale (HAM-D17) has been widely adopted to define remission of depression, a full recovery from depression is closely related to the patient's quality of life as well. Accordingly, we re-evaluated this definition of remission using HAM-D17 in comparison with the corresponding score for health-related quality of life (HRQOL) measured by the SF-36., Methods: Using the data for depressive patients reported by GlaxoSmithKline K.K. (Study No. BRL29060A/863) in a post-marketing observational study of paroxetine, with a sample size of n = 722, multivariate logistic regression was performed with the HAM-D17 score as a dependent variable and with each of the eight domain scores of HRQOL (from the SF-36) transformed into a binominal form according to the national standard value for Japan. Then, area under curve of receiver operating characteristic analyses were conducted. Based on the obtained results, a multivariate analysis was performed using the HAM-D17 score in a binomial form with HAM-D17 as a dependent variable and with each of the eight HRQOL domain scores (SF-36) as binominalized independent variables., Results: A cutoff value for the HAM-D17 score of 5 provided the maximum ROC-AUC at "0.864." The significantly associated scores of the eight HRQOL domains (SF-36) were identified for the HAM-D17 cutoff values of ≥5 and ≤4. The scores for physical functioning (odds ratio, 0.473), bodily pain (0.557), vitality (0.379), social functioning (0.540), role-emotion (0.265), and mental health (0.467) had a significant negative association with the HAM-D17 score (p < 0.05), and HRQOL domain scores for HAM-D17 ≥ 5 were significantly lower compared with those for HAM-D17 ≤ 4., Conclusions: A cutoff value for HAM-D17 of less than or equal to 4 was the best candidate for indicating remission of depression when the recovery of HRQOL is considered. Restoration of social function and performance should be considered equally important in assessing the adequacy of treatment for patients with depression.

Brexpiprazole is currently approved in the United States for the treatment of schizophrenia and as adjunctive treatment of major depressive disorder. In Canada, it is approved for the treatment of schizophrenia. This study evaluated the pharmacokinetics (PK) and safety of brexpiprazole in Japanese patients with schizophrenia. This phase 1 study comprised a 14-day multiple-dose administration of brexpiprazole 1, 4, and 6 mg/day (n = 7, 8, and 6, respectively). Plasma concentrations and PK parameters and the influence of CYP2D6 polymorphisms (intermediate metabolizers [IMs] and extensive metabolizers [EMs]) on PK were evaluated. Adverse events (AEs) were recorded. The C max and AUC 24h of brexpiprazole and its metabolite, DM-3411, showed dose-proportionality. The C max and AUC 24h of brexpiprazole showed accumulation of about 2.5- to 5.5-fold on day 14, compared with those on day 1. The median t max and the mean elimination half-life of brexpiprazole were 4-5 and 52-92 hours, respectively, across all doses on day 14. The C 24h of brexpiprazole reached steady state after day 10 in all dose groups. The dose-normalized C max and AUC 24h of brexpiprazole on day 14 were higher in IM patients than in EM patients. AEs were generally mild to moderate, with transient serum prolactin increase being the most common event. No clinically significant changes were observed for other clinical laboratory values. Brexpiprazole was safe and well tolerated in the studied Japanese patients with schizophrenia., (© 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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.

Clozapine has improved efficacy relative to typical antipsychotics in schizophrenia treatment, particularly regarding emotional symptoms. However, the mechanisms underlying its therapeutic benefits remain unclear. Using a methamphetamine-sensitised rat model, we measured changes in dopamine levels in the amygdalae in response to a fear-conditioned cue, serving as a biochemical marker of emotional cognitive processing disruption in psychosis, for analysing the biochemical mechanisms associated with the clinical benefits of clozapine. We also compared how clozapine and haloperidol affected basal dopamine levels and phasic dopamine release in response to the fear-conditioned cue. Extracellular dopamine was collected from the amygdalae of freely moving rats via microdialysis and was analysed by high-performance liquid chromatography. Clozapine or haloperidol was injected during microdialysis, followed by exposure to the fear-conditioned cue. We analysed the ratio of change in dopamine levels from baseline. Haloperidol treatment increased the baseline dopamine levels in both non-sensitised and sensitised rats. Conversely, clozapine only increased the basal dopamine levels in the non-sensitised rats, but not in the sensitised rats. Although both antipsychotics attenuated phasic dopamine release in both the non-sensitised and sensitised rats, the attenuation extent was greater for clozapine than for haloperidol under both dopaminergic conditions. Our findings indicate that stabilized dopamine release in the amygdalae is a common therapeutic mechanism of antipsychotic action during emotional processing. However, the specific dopaminergic state-dependent action of clozapine on both basal dopamine levels and stress-induced dopamine release may be the underlying mechanism for its superior clinical effect on emotional cognitive processing in patients with schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.

Background: Previously, we applied basic group theory and related concepts to scales of measurement of clinical disease states and clinical findings (including laboratory data). To gain a more concrete comprehension, we here apply the concept of matrix representation, which was not explicitly exploited in our previous work., Methods: Starting with a set of orthonormal vectors, called the basis, an operator Rj (an N-tuple patient disease state at the j-th session) was expressed as a set of stratified vectors representing plural operations on individual components, so as to satisfy the group matrix representation., Results: The stratified vectors containing individual unit operations were combined into one-dimensional square matrices [Rj]s. The [Rj]s meet the matrix representation of a group (ring) as a K-algebra. Using the same-sized matrix of stratified vectors, we can also express changes in the plural set of [Rj]s. The method is demonstrated on simple examples., Conclusions: Despite the incompleteness of our model, the group matrix representation of stratified vectors offers a formal mathematical approach to clinical medicine, aligning it with other branches of natural science.

Background: We previously presented a group theoretical model that describes psychiatric patient states or clinical data in a graded vector-like format based on modulo groups. Meanwhile, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, the current version), is frequently used for diagnosis in daily psychiatric treatments and biological research. The diagnostic criteria of DSM-5 contain simple binominal items relating to the presence or absence of specific symptoms. In spite of its simple form, the practical structure of the DSM-5 system is not sufficiently systemized for data to be treated in a more rationally sophisticated way. To view the disease states in terms of symmetry in the manner of abstract algebra is considered important for the future systematization of clinical medicine., Results: We provide a simple idea for the practical treatment of the psychiatric diagnosis/score of DSM-5 using depressive symptoms in line with our previously proposed method. An expression is given employing modulo-2 and -7 arithmetic (in particular, additive group theory) for Criterion A of a 'major depressive episode' that must be met for the diagnosis of 'major depressive disorder' in DSM-5. For this purpose, the novel concept of an imaginary value 0 that can be recognized as an explicit 0 or implicit 0 was introduced to compose the model. The zeros allow the incorporation or deletion of an item between any other symptoms if they are ordered appropriately. Optionally, a vector-like expression can be used to rate/select only specific items when modifying the criterion/scale. Simple examples are illustrated concretely., Conclusions: Further development of the proposed method for the criteria/scale of a disease is expected to raise the level of formalism of clinical medicine to that of other fields of natural science.

Objective: To compare the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) for detecting post-cardiac surgery delirium., Background: These tools have not been tested in a specialized cardio-surgical ICU., Methods: Sensitivities and specificities of each tool were assessed in a cardio-surgical ICU in Japan by two trained nurses independently. Results were compared with delirium diagnosed by psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision., Results: There were 110 daily, paired assessments in 31 patients. The CAM-ICU showed 38% sensitivity and 100% specificity for both nurses. All 20 false-negative cases resulted from high scores in the auditory attention screening in CAM-ICU. The ICDSC showed 97% and 94% sensitivity, and 97% and 91% specificity for the two nurses (cutoff ≥4)., Conclusion: In a Japanese cardio-surgical ICU, the ICDSC had a higher sensitivity than the CAM-ICU., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: A number of animal studies have implicated circadian clock genes in the regulation of mood, anxiety, and reward. However, the effect of misalignment of the environmental light-dark and internal circadian clock on the monoamine system is not fully understood. In the present study, we examined whether an abnormal light-dark schedule would affect behavior-, circadian clock-, and monoamine-related gene expressions, along with monoamine contents in the amygdala and hippocampus of mice., Methods: Mice were subjected to an 8-hour phase delay in the light-dark cycle (Shift) every two days for four weeks, and locomotor activity was continuously measured. We examined the circadian expression of clock genes (Per1, Per2, and Bmal1) and genes of the NE/5HT uptake transporters (Net and Sert). In addition, the levels of NE/5HT and their metabolites MHPG/5HIAA were analyzed in the amygdala and hippocampus., Results: Locomotor activity showed a free-running phenotype with a longer period (>24 hours) and showed misalignment between the light-dark and inactive-active cycles. The amplitude of the day-night fluctuation of Bmal1 expression was reduced in the amygdala and hippocampus of light-dark-shifted mice. Net gene expression in the Shift group showed different profiles compared with the Control group. In addition, NE and 5HT levels in the amygdala of the Shift group increased during the active period., Conclusions: The present results suggest that misalignment of the internal and external clocks by continuous shifting of the light-dark cycle affects the circadian clocks and monoamine metabolism in the amygdala and hippocampus of mice., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Although the results of previous studies have suggested that disruptions in circadian rhythms are involved in the pathogenesis of depression, no studies have examined the interaction of clock gene expression deficit and depression state. In this study, we examined clock gene expression levels and depressive-like behavior in mice housed under 3.5h light, 3.5h dark (T = 7) conditions to investigate the association between clock gene expression and depressive state. C57BL/6J mice were housed under a T = 24 cycle (12h light, 12h dark) or a T = 7 cycle and clock gene expression levels in the hippocampus and the amygdala were measured by real-time RT-PCR. Depressive state was evaluated by the forced swim test (FST). Although circadian rhythms of Per1 and Per2 clock gene expression in the hippocampus and amygdala were still detected under T = 7 conditions, rhythmicity and expression levels of both significantly decreased. Mice housed with a T = 7 cycle showed increased immobile time in the FST than those with a T = 24 cycle. The present results suggest that the presence of a depressive state around the early active phase of activity may be related to impairment of rhythmicity and expression levels of Per1 and Per2 genes under abnormal light-dark conditions., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Narcolepsy without cataplexy (NA w/o CA) (narcolepsy type 2) is a lifelong disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, but no cataplexy. In the present study, we examined the human leukocyte antigen HLA-DQB1 in 160 Japanese patients with NA w/o CA and 1,418 control subjects. Frequencies of DQB1*06:02 were significantly higher in patients with NA w/o CA compared with controls (allele frequency: 16.6 vs. 7.8%, P=1.1×10(-7), odds ratio (OR)=2.36; carrier frequency: 31.3 vs. 14.7%, P=7.6×10(-8), OR=2.64). Distributions of HLA-DQB1 alleles other than DQB1*06:02 were compared between NA w/o CA and narcolepsy with cataplexy (NA-CA) to assess whether the genetic backgrounds of the two diseases have similarities. The distribution of the HLA-DQB1 alleles in DQB1*06:02-negative NA w/o CA was significantly different from that in NA-CA (P=5.8×10(-7)). On the other hand, the patterns of the HLA-DQB1 alleles were similar between DQB1*06:02-positive NA w/o CA and NA-CA. HLA-DQB1 analysis was also performed in 186 Japanese patients with idiopathic hypersomnia (IHS) with/without long sleep time, but no significant associations were observed.

Objective: Norepinephrine is an important chemical messenger that is involved in mood and stress in humans, and is reabsorbed by the norepinephrine transporter (NET). According to Cloninger's theory, the noradrenergic system mediates the personality trait of reward dependence. Thus far, although association studies on NET gene polymorphisms and Cloninger's personality traits have been reported, they yielded inconsistent results. Therefore, in the present study we investigated whether or not the 1287G/A, -182T/C and -3081A/T polymorphisms of the NET gene (SLC6A2) are associated with reward dependence-related traits, as assessed by the five-factor model., Methods: After written informed consent was obtained from participants, the three NET gene polymorphisms were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), and personality was assessed by the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) in 270 Japanese university students., Results: A significant relation was found between the -3081A/T functional promoter polymorphism and NEO-FFI scores: those with the T allele exhibited a lower extraversion (E) score than those without the T allele (Mann-Whitney U-test: z=-3.861, p<0.001). However, there was no correlation between the other NET gene polymorphisms and E score, and no association with other dimensions and these three polymorphisms., Conclusion: We conclude that the -3081A/T functional polymorphism in the NET gene may affect the extraversion of reward dependence-related traits, as measured by NEO-FFI. However, we used only the shortened version of NEO-PI-R in this study. Further investigations are necessary using the full version of self-rating personality questionnaires.

Schizophrenia and bipolar disorder show high comorbidity with smoking dependence. Several previous studies reported that glycogen synthase kinase 3β (GSK3β), which is widely expressed in the brain including the dopamine projection areas such as the amygdala, nucleus accumbens and hippocampus, may play a role in neuropsychiatric disorders and dopamine- and serotonin-mediated behavior. In this study, we have analyzed the association of three single nucleotide polymorphisms (SNPs) within GSK3β gene (rs3755557, rs334558, rs6438552) with the smoking habits and age at smoking initiation in a sample of 384 young adult Japanese, which included 172 smokers and 212 non-smokers. As a result, rs334558 was significantly associated with smoking habits in genotype frequency and allelic frequency (P < 0.05). Furthermore, higher haplotype 3 (T-T-T) and haplotype 5 (A-T-C) frequencies were observed in non-smokers than smokers (P < 0.05). Three functional polymorphisms examined in this study reportedly increase transcriptional activity when they have a high-activation allele such as the A allele of -1727A/T (rs3755557), the T allele of -50T/C (rs334558) or T allele of -157T/C (rs6438552). Thus, it was suggested in this study that changes in GSK3β activity may have an impact on smoking habits.

Objective: Neurocognitive impairment (NCI) has been intensively studied in patients with systemic lupus erythematosus (SLE). However, those studies have mostly included patients who were treated with corticosteroids, which may itself induce NCI. We investigated NCI in corticosteroid-naive people with SLE who did not exhibit any overt neuropsychiatric manifestations., Methods: Forty-three inpatients with SLE who had no current or past neuropsychiatric history participated in the study. Patients and 30 healthy control subjects with similar demographic characteristics were given a 1-h battery of neuropsychological tests. NCI was defined as scores at least 2 SD below the mean of the healthy control group on at least 2 of the 7 neurocognitive domains. Results of clinical, laboratory, and neurologic tests were compared regarding the presence of NCI., Results: NCI was identified in 12 patients (27.9%) with SLE and in 2 control subjects (6.7%). Patients with SLE showed a significant impairment compared with controls on tasks assessing immediate recall, complex attention/executive function, and psychomotor speed. We identified psychomotor speed (Digit Symbol Substitution Test) as the factor that best differentiated the 2 groups. Further, we identified the score of the SLE Disease Activity Index 2000 as an independent risk factor for NCI in patients with SLE., Conclusion: We conclude that reduced psychomotor speed is an SLE-specific pattern of NCI. Verbal-memory deficits that have been reported in patients with SLE were not evident among patients who were corticosteroid-naive. Our results indicate that impaired psychomotor speed may be added to the symptoms of early SLE.

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: This study was designed to evaluate efficacy and safety of aripiprazole once-monthly (AOM) by verifying non-inferiority of AOM to oral aripiprazole in Asian patients with schizophrenia., Method: The study consisted of a screening phase and three phases: an oral conversion phase (≤12weeks), an oral stabilization phase (≤12weeks) and a 52-week double-blind phase. Patients meeting stabilization criteria for 4weeks during the oral stabilization phase were randomly assigned (1:1) to AOM (400mg) or oral aripiprazole (6-24mg/day). The primary endpoint was Kaplan-Meier estimated rate of non-exacerbation of psychotic symptoms/non-relapse at Week 26., Results: A total of 724 patients were screened, and 502 patients entered the oral stabilization phase. Of 455 patients randomized in the double-blind phase, 228 received AOM and 227 received oral aripiprazole. The non-exacerbation of psychotic symptoms/non-relapse rates at Week 26 were 95.0% (AOM) and 94.7% (oral aripiprazole) and the difference was 0.3% (95% CI: -3.9,4.5), thus non-inferiority of AOM compared to oral aripiprazole with respect to non-exacerbation of psychotic symptoms/non-relapse rate was shown with a margin of -3.9% which is well above the pre-defined non-inferiority limit (-15%). The proportions of patients meeting exacerbation of psychotic symptoms/relapse criteria and stabilization of psychotic symptoms/maintenance criteria were 6.6% and 92.5% in both groups. Discontinuation rates due to all reasons were 25.9% (AOM) and 33.5% (oral aripiprazole). AOM was well tolerated as well as oral aripiprazole., Conclusions: Non-inferiority of AOM to oral aripiprazole was established. AOM is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole., Clinical Trials Registration: JapicCTI-101175., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Epigenetic regulation may be involved in the pathophysiology of mental disorders, such as schizophrenia and bipolar disorder, and in the pharmacological action of drugs. Characterizing the epigenetic effects of drugs is an important step to optimal treatment. We performed comprehensive and gene-specific DNA methylation analyses of quetiapine using human neuroblastoma cells. Human neuroblastoma cells were cultured with quetiapine for 8 days, and DNA methylation analysis was performed using Infinium HumanMethylation27 BeadChip. A total of 1173 genes showed altered DNA methylation. Altered DNA methylation predominantly occurred as hypomethylation within the CpG island compared to DNA isolated from non-treated cells. Gene ontology analysis revealed that these genes were related to the cellular process of intracellular protein binding. There was no common effect of quetiapine with three mood stabilizers (lithium, valproate, and carbamazepine). However, common DNA methylation changes in eight genes, including ADRA1A, which encodes adrenoceptor alpha 1A, were found with quetiapine and lithium treatments. Finally, bisulfite-sequencing analysis revealed that quetiapine decreased the DNA methylation level of the promoter region of SLC6A4, where hypermethylation with bipolar disorder and hypomethylation with mood stabilizers have been reported., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Anxiety is often present in patients with depression. The aim of this study was to evaluate the impact of clustered depression and anxiety on mortality and rehospitalization in hospitalized patients with heart failure (HF)., Methods: A total of 221 hospitalized patients with HF, who completed the questionnaires, were analyzed in this prospective study (mean age 62±13 years; 28% female). One-third patients had implanted cardiac devices. Depression was defined as a Zung Self-Rating Depression Scale index score of ≥60 and anxiety was defined as a State-Trait Anxiety Inventory score of ≥40 (male) or ≥42 (female). The primary outcome was the composite of death from any cause or rehospitalization due to worsened HF and refractory arrhythmia., Results: Of the 221 HF patients, 29 (13%) had depression alone, 80 (36%) had anxiety alone, and 46 patients (21%) had both depression and anxiety. During an average follow-up of 41±21 months, patients with depression alone and those with clustered depression and anxiety were at an increased risk of the primary outcome [hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.17-4.28, p=0.01 and HR 2.75, 95% CI: 1.51-4.99, p=0.01, respectively] compared to patients with no symptoms. Multivariate analysis after adjusting for age, gender, New York Heart Association functional class, B-type natriuretic peptide, device implantation, renal dysfunction, and left ventricular dysfunction showed clustered depression and anxiety, but not depression alone or anxiety alone, was an independent predictor of the primary outcome (HR 1.96, 95% CI: 1.00-3.27, p=0.04)., Conclusions: Our results showed that clustered depression and anxiety were associated with worse outcomes in patients with HF., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)