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Jun Ishigooka,1 Tatsuya Hoshino,2 Takumi Imai,3 Hisako Yoshida,3 Midori Ono,2 Mihoko Ota,2 Yoshiya Moriguchi,4 Keita Fujikawa,2 Ayumi Shintani,3 Jovelle L Fernandez2 1Institute of CNS Pharmacology, Tokyo, Japan; 2Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan; 3Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan; 4Medical Affairs, Lundbeck Japan K.K., Tokyo, JapanCorrespondence: Tatsuya HoshinoJapan Medical Office, Takeda Pharmaceutical Company Limited, 1-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo, 103-8668, JapanTel +81 3 3278 2111Fax +81 3 3278 2925Email tatsuya.hoshino@takeda.comPurpose: A previous international study suggested that perceptions of depression symptoms, social function, and treatment expectations are different between patients/physicians. We aimed to examine whether such differences exist in Japan.Methods: A web-based survey was conducted with patients who reported that they had been diagnosed with depression, and physicians who reported that they had treated patients with depression, in Japan. Questionnaires were designed to quantify patients’ perceptions of symptoms, social function, and treatment expectations. Patients were categorized into three stages of disorder based on their reported current symptoms: severe symptomatic, mild symptomatic, and remission. Physicians were assigned up to three patients, were provided with patient information from the questionnaire completed by those patients, and finally the completed questionnaire forms for each patient. Agreement between the perceptions of the patients and physicians was examined for each stage.Results: Of the 2618 eligible patients, 828 were assigned to 326 eligible physicians. Overall, we found small differences in the perceptions of depression treatment between patients/physicians. Slightly fewer physicians than patients reported physical symptoms (85% vs 91%; p=0.018) in the mild symptomatic stage. Fewer physicians than patients reported cognitive symptoms in the severe (82% vs 87%; p=0.029) and mild (54% vs 66%; p=0.003) symptomatic stages. Social function was deemed to be lower by physicians than by patients, across all stages of disorder (p< 0.001). Regarding treatment expectations, more physicians than patients reported “return to a normal life” in the mild symptomatic (51% vs 35%, p< 0.001) and remission stages (57% vs 36%, p< 0.001), and more patients than physicians reported “reduction of side effects” in the severe (10% vs 4%, p=0.004) and mild (12% vs 5%, p< 0.001) symptomatic disorder stages.Conclusion: These results suggest small differences in patient/physician perceptions of depression treatment in Japan. Discrepancies between patients’/physicians’ perceptions may vary depending on the medical environment.Keywords: depression, perception, patient, physician, web-based survey

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

Ken Inada,1 Sakiko Yamada,2 Hisashi Akiyoshi,2 Yoshitsugu Kojima,2 Shuichi Iwashita,3 Jun Ishigooka4 1Department of Psychiatry, Tokyo Women’s Medical University, Tokyo, Japan; 2Department of Medical Affairs, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan; 3Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., Osaka, Japan; 4Institute of CNS Pharmacology, Tokyo, JapanCorrespondence: Sakiko Yamada Department of Medical AffairsOtsuka Pharmaceutical Co, Ltd., Shinagawa Grand Central Tower, 2-6-14 Konan, Minato-Ku, Tokyo 108-8242, JapanTel +81-3-6717-1400Fax +81-3-6717-1398Email yamadasa@otsuka.jpPurpose: 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, < 65).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.Keywords: brexpiprazole, long-term, schizophrenia, elderly, safety, Japanese

Hiroko Sugawara,1 Takahiro Tsutsumi,2 Ken Inada,2 Jun Ishigooka,2 Mamoru Hashimoto,1 Minoru Takebayashi,1,3 Katsuji Nishimura2 1Department of Neuropsychiatry, Faculty of Life Science, Kumamoto University, Kumamoto, Japan; 2Department of Psychiatry, Tokyo Women’s Medical University Hospital, Tokyo, Japan; 3Division of Psychiatry and Neuroscience, Institute for Clinical Research, National Hospital Organization Kure Medical Center, Hiroshima, Japan Purpose: Mixed features in a major depressive episode (MDE) predict bipolar disorder (BD). The mixed features specifier included in the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) could be restrictive because it excludes the symptoms common to both mania/hypomania and depression, including psychomotor agitation. On the other hand, an anxious distress (ANXD) specifier has also been introduced in the DSM-5, and psychomotor agitation has been defined as a severity of ANXD. In this study, we retrospectively investigated the association between presence of ANXD in an MDE and bipolarity. Patients and methods: The subjects were patients admitted with an MDE to the Department of Psychiatry at Tokyo Women’s Medical University Hospital from December 2014 to March 2016. Eligible patients were older than 20 years of age and met the DSM-5 criteria for major depressive disorder or BD. All data were extracted from medical records. The subjects were grouped according to whether they did or did not have ANXD. The demographics and clinical features of these groups were compared. Severity of illness was evaluated according to the Hamilton Rating Scale for Depression (HRSD) score on admission. Results: ANXD was present in 31 and absent in 33 of 64 patients with MDE. The HRSD score was significantly higher in the group with ANXD than in the group without ANXD (P=0.0041). Mixed features (P=0.0050) and suicide attempts (P=0.0206) were significantly more common in the group with ANXD than in the group without ANXD. Conclusion: We found that the presence of ANXD in an MDE was associated with greater severity and more mixed features and suicide attempts. It is important to evaluate a patient with an MDE for ANXD so that a diagnosis of mixed depression is not missed. More studies in larger samples are needed to investigate further the association between ANXD in MDE and bipolarity. Keywords: anxious distress, mixed features, major depressive episode, bipolarity

Takahiro Tsutsumi,1 Hiroko Sugawara,1,2 Ryoko Ito,1 Mizuho Asano,1 Satoru Shimizu,3 Jun Ishigooka,1 Katsuji Nishimura1 1Department of Psychiatry, 2Support Center for Women Health Care Professionals and Research, 3Department of Research, Medical Research Institute, Tokyo Women’s Medical University, Tokyo, Japan Background: Mirtazapine, which is classified as a noradrenergic and specific serotonergic antidepressant, is widely prescribed for the treatment of major depressive disorder. The potential predictive factors of the efficacy of mirtazapine and the tolerability based on the incidence of oversedation and jitteriness/anxiety syndrome were evaluated. Patients and methods: Patients with major depressive disorder were retrospectively investigated. Study subjects comprised 68 patients with depression who received mirtazapine as an initial antidepressant at the Department of Psychiatry of the Tokyo Women’s Medical University Hospital from September 2009 to March 2013. The efficacy of mirtazapine monotherapy was evaluated based on the Clinical Global Impression Improvement score. Clinical characteristics were compared between remission and nonremission groups to determine the factors predicting the efficacy. Moreover, discontinuation rates due to adverse effects, including oversedation and jitteriness/anxiety syndrome, were examined, and the effects of confounding factors were evaluated. Results: The remission rate of mirtazapine monotherapy was 36.8% among the 68 enrolled subjects. The mean final doses in the remission and nonremission groups were 27.6±13.5 mg and 26.0±14.1 mg, respectively, and there was no significant difference between them. Multiple logistic analyses revealed that the absence of guilt (odds ratio [OR] =0.15; 95% CI [1.66–37.24], P=0.006) and the presence of psychomotor retardation (OR =4.30; 95% CI [1.30–16.60], P=0.016) were significantly related to the efficacy of mirtazapine monotherapy. The discontinuation rates due to oversedation and jitteriness/anxiety syndrome were 13.2% and 11.8%, respectively. Age did not differ significantly between patients with or without oversedation or jitteriness/anxiety syndrome (P=0.078 and P=0.579, respectively). Conclusion: The absence of guilt and the presence of psychomotor retardation may predict the efficacy of mirtazapine, and mirtazapine may be tolerable for all ages. Keywords: feelings of guilt, psychomotor retardation, oversedation, jitteriness, anxiety syndrome

Hiroko Sugawara,1,2 Kaoru Sakamoto,1 Tsuyoto Harada,3 Satoru Shimizu,4 Jun Ishigooka1 1Department of Psychiatry, Tokyo Women’s Medical University, 2Support Center for Women Health Care Professionals and Researchers, Tokyo Women’s Medical University, Shinjuku-ku, 3Department of Psychiatry, Tokyo Women’s Medical University Medical Center East, Arakawa-ku, 4Department of Research, Medical Research Institute, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan Background: Several studies have evaluated the efficacy and tolerability of aripiprazole for augmentation of antidepressant therapy for treatment-resistant depression (TRD). Here, we investigated the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder and the clinical predictors of treatment efficacy in a Japanese population. Methods: Eighty-five depressed Japanese patients who underwent aripiprazole augmentation therapy after failing to respond satisfactorily to antidepressant monotherapy were included in the study. Treatment responses were evaluated based on Clinical Global Impression Improvement scores assessed 8 weeks after initiation of aripiprazole administration. We compared demographic and diagnostic variables, psychiatric medication variables, and clinical variables between remission and nonremission groups. Results: The aripiprazole augmentation remission rate was 36.5%. Multiple logistic regression analysis indicated that aripiprazole augmentation was significantly more effective for bipolar depression than for major depressive disorder, and both absence of comorbid anxiety disorders and current episode duration >3 months were significantly associated with the efficacy of aripiprazole augmentation. Conclusion: Polarity of depression, comorbidity of anxiety disorders, and current episode duration may predict the efficacy of aripiprazole augmentation for TRD including both major depressive disorder and bipolar disorder. Among them, comorbidity of anxiety disorders was significantly related to the efficacy for TRD including only major depressive disorder. Additional studies are needed to examine the association between the efficacy of aripiprazole augmentation and bipolarity, and these findings should be validated further in a prospective study. Keywords: TRD, aripiprazole, predictor, bipolar depression, anxiety disorder

Akitsugu Sueki, Eriko Suzuki, Hitoshi Takahashi, Jun Ishigooka Department of Neuropsychiatry, Tokyo Women’s Medical University, Tokyo, Japan Purpose: In this prospective study, we examined whether early reduction in depressive symptoms predicts later remission to duloxetine in the treatment of depression, as monitored using the Montgomery–Asberg Depression Rating Scale (MADRS). Patients and methods: Among the 106 patients who were enrolled in this study, 67 were included in the statistical analysis. A clinical evaluation using the MADRS was performed at weeks 0, 4, 8, 12, and 16 after commencing treatment. For each time point, the MADRS total score was separated into three components: dysphoria, retardation, and vegetative scores. Results: Remission was defined as an MADRS total score of ≤10 at end point. From our univariate logistic regression analysis, we found that improvements in both the MADRS total score and the dysphoria score at week 4 had a significant interaction with subsequent remission. Furthermore, age and sex were significant predictors of remission. There was an increase of approximately 4% in the odds of remission for each unit increase in age, and female sex had an odds of remission of 0.318 times that of male sex (remission rate for men was 73.1% [19/26] and for women 46.3% [19/41]). However, in the multivariate model using the change from baseline in the total MADRS, dysphoria, retardation, and vegetative scores at week 4, in which age and sex were included as covariates, only sex retained significance, except for an improvement in the dysphoria score. Conclusion: No significant interaction was found between early response to duloxetine and eventual remission in this study. Sex difference was found to be a predictor of subsequent remission in patients with depression who were treated with duloxetine, with the male sex having greater odds of remission. Keywords: antidepressant, early response, sex difference, serotonin–noradrenalin reuptake inhibitor

Tsuyoto Harada, Ken Inada, Kazuo Yamada, Kaoru Sakamoto, Jun Ishigooka Department of Psychiatry, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan Objective: Patients often develop neuropsychiatric symptoms such as anxiety and agitation after they have started taking an antidepressant, and this is thought to be associated with a potentially increased risk of suicide. However, the incidence of antidepressant-induced jitteriness/anxiety syndrome has not been fully investigated, and little has been reported on its predictors. The aim of this study was to survey the incidence of antidepressant-induced jitteriness/anxiety syndrome and clarify its predictors in a natural clinical setting.Materials and methods: Between January 2009 and July 2012, we prospectively surveyed 301 patients who had not taken any antidepressants for 1 month before presentation, and who were prescribed antidepressants for 1 month after their initial visit. Patients were classified as developing antidepressant-induced jitteriness/anxiety syndrome if they experienced any symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, or mania during the first month.Results: Among the 301 patients, 21 (7.0%) developed antidepressant-induced jitteriness/anxiety syndrome. Major depressive disorder and a diagnosis of mood disorder in first-degree relatives of patients were significantly associated with induction of antidepressant-induced jitteriness/anxiety syndrome (odds ratio 10.2, P=0.001; odds ratio 4.65, P=0.02; respectively). However, there was no such relationship for sex, age, class of antidepressant, combined use of benzodiazepines, or diagnosis of anxiety disorder.Conclusion: The findings of this study suggest that major depressive disorder and a diagnosis of mood disorder in first-degree relatives may be clinical predictors of antidepressant-induced jitteriness/anxiety syndrome.Keywords: side effects, antidepressants, selective serotonin-reuptake inhibitors, tricyclic antidepressive agents, suicide

Objective Psychological distress, such as depression and anxiety, has been intensively studied in patients with systemic lupus erythematosus (SLE). However, those studies have mostly included patients who were treated with corticosteroids, which might themselves induce mood disturbances. We investigated psychological distress in corticosteroid-naive patients with SLE who did not exhibit any overt neuropsychiatric manifestations. Methods Forty-three SLE in-patients with no current or past abnormal neuropsychiatric history participated in the study. Patients and 30 healthy control subjects with similar demographic and personality characteristics were administered a comprehensive battery of psychological/neuropsychological tests. The Profile of Mood States (POMS) was used to assess depression and anxiety. Results of clinical, laboratory, and neurological tests were compared with regard to their presence. Results Prevalence of depression was higher in patients (n = 11, 25.6%) than in controls (n = 2, 6.7%; p = 0.035), although prevalence of anxiety did not differ across groups (patients: 34.9%, n = 15; controls: 16.7%, n = 5; p = 0.147). Using multiple logistic regression analysis, we identified avoidance coping methods (OR, 1.3; 95% CI 1.030–1.644; p = 0.027) as an independent risk factor for depression. Conclusion Our results indicate that depression presents more frequently in corticosteroid-naive patients with early-stage, active SLE than in the normal population, but anxiety does not. Depression may be related to psychological reactions to suffering from the disease. [ABSTRACT FROM AUTHOR]

Objective: Clonazepam has been shown to be an effective supplementary treatment for depression. Thus, it would be useful to determine the characteristics associated with response to clonazepam therapy in patients with depression. The purpose of this study was to examine the time to onset of action and the patient's response with respect to psychiatric symptom in the treatment of clonazepam cotherapy. Design: A retrospective cohort analysis was carried out among protracted depression patients. Methods. One hundred and thirty-four patients with protracted depression were being treated with clonazepam. Results. Sixty-eight patients (50.8%) responded to clonazepam cotherapy. After 2 weeks, the cumulative percentage of responders was 80%. There was no difference in the response of protracted depression patients who had inhibited and agitated symptoms (x2= 0.878, df = 2, P = 0.6442). Conclusion. The above findings can help guide clinicians in the use of clonazepam augmentation therapy for protracted depression. [ABSTRACT FROM AUTHOR]

Abstract Background Although the Brief Psychiatric Rating Scale (BPRS) is widely used for evaluating patients with schizophrenia, it has limited value in estimating the clinical weight of individual symptoms. The aim of this study was 4-fold: 1) to investigate the relationship of the BPRS to the Clinical Global Impression-Schizophrenia Scale (CGI-SCH), 2) to express this relationship in mathematical form, 3) to seek significant symptoms, and 4) to consider a possible modified BPRS subscale. Methods We evaluated 150 schizophrenia patients using the BPRS and the CGI-SCH, then examined the scatter plot distribution of the two scales and expressed it in a mathematical equation. Next, backward stepwise regression was performed to select BPRS items that were highly associated with the CGI-SCH. Multivariate regression was conducted to allocate marks to individual items, proportional to their respective magnitude. We assessed the influence of modifications to the BPRS in terms of Pearson's r correlation coefficient and r-squared to evaluate the relationship between the two scales. Utilizing symptom weighting, we assumed a possible BPRS subscale. Results By plotting the scores for the two scales, a logarithmic curve was obtained. By performing a logarithmic transformation of the BPRS total score, the curve was modified to a linear distribution, described by [CGI-SCH] = 7.1497 × log10[18-item BPRS] - 6.7705 (p < 0.001). Pearson's r for the relationship between the scales was 0.7926 and r-squared was 0.7560 (both p < 0.001). Applying backward stepwise regression using small sets of items, eight symptoms were positively correlated with the CGI-SCH (p < 0.005) and the subset gave Pearson's r of 0.8185 and r-squared of 0.7198. Further selection at the multivariate regression yielded Pearson's r of 0.8315 and r-squared of 0.7036. Then, modification of point allocation provided Pearson's r of 0.8339 and r-squared of 0.7036 (all these p < 0.001). A possible modified BPRS subscale, "the modified seven-item BPRS", was designed. Conclusions Limited within our data, a logarithmic relationship was assumed between the two scales, and not only individual items of the BPRS but also their weightings were considered important for a linear relationship and improvement of the BPRS for evaluating schizophrenia.

Background: We report the final results of treatment with aripiprazole, blonanserin, and paliperidone from the Japan Useful Medication Program for Schizophrenia (JUMPs), a 104-week naturalistic study., Methods: JUMPs was an open-label, three-arm, randomized, parallel-group, 104-week study. Patients aged ≥ 20 years with schizophrenia requiring antipsychotic treatment or a switch from previous therapy were enrolled. The primary endpoint was treatment discontinuation rate over 104 weeks. Secondary endpoints included remission rate, Personal and Social Performance (PSP), safety, Positive and Negative Syndrome Scale (PANSS), and quality of life (QOL; EuroQol-5 dimension)., Results: In total, 251 patients received aripiprazole (n = 82), blonanserin (n = 85), or paliperidone (n = 84). Treatment discontinuation rates (aripiprazole, 80.5%; blonanserin, 81.2%; paliperidone, 71.4%) were not significantly different (p = 0.2385) among the treatment groups at 104 weeks; comparable outcomes were observed for endpoints, including remission (42.9%, 46.7%, and 45.8%), PANSS, and safety. In the overall cohort, while the improvement in the PSP total score at Week 104 was not significantly different from baseline, a significant improvement (p < 0.05) in QOL and total PANSS scores (including all subscales) was observed at Week 104 compared with baseline. Multivariable analysis identified a shorter disease duration and a higher chlorpromazine-equivalent antipsychotic dosage level (≥ 1000 mg) before switching to monotherapy as predictors of treatment discontinuation., Conclusions: The 104-week treatment outcomes were comparable between groups; the overall trend of improvement in remission rate, safety, and QOL suggests the importance of continued treatment., Clinical Trial Registration: UMIN-Clinical Trials Registry UMIN000007942 (public release date: 14/05/2012)., (© 2024. The Author(s).)

algebraic concepts such as category are considered cornerstones on which logical consistency relies in any sophisticated study of natural phenomena. However, to the best of our knowledge, in molecular/genetic biology, their application is still severely limited because they capture neither the dynamics nor provide a visual form. The Petri net (PN) has often been used to illustrate visually parallel, asynchronous dynamic events in small data systems. A prototypal hybrid model combining both category theory and extended PNs may instead be indispensable for that purpose. This hybrid model incorporates 1) token-like elements of a group, 2) object-like places of a category, 3) square poles (rather than pentagon poles) that enable unique identifications of single-strand DNA sequences from the shape of its polygonal line, 4) creation/annihilation morphisms that generate/erase tokens, 5) Cartesian products 'Z5×Z2×…' that enable conversions between DNA and RNA sequences, 6) somatic recombinations (VDJ recombinations) for antibodies displayed concretely in category-theoretic form, 7) 'identity protein Δ' translated from a triplet of identity bases 'EEE' as an advanced concept from our previous display of the canonical central dogma, 8) illustrations of an incidence-matrix-like matrix A that includes operators as coordinates, and 9) basic topics concerning the canonical central dogma being displayed concretely using concepts of conventional category theory such as 'adjoint', 'adjoint functor', 'natural transformation', 'Yoneda's lemma' and 'Kan extension'. These ideas provide more advanced tools that expand our previous model concerning nucleic-acid-base sequences. Despite the nascent nature of our methodology, our hybrid model has potential in a variety of applications, illustrated using molecular/genetic sequences, in particular providing a simple dynamic/visual representation. With further improvements, this approach may prove effective in reducing the need for large data-storing systems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sawamura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aim: The therapeutic potential of N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK-801), a highly selective NMDAR antagonist., Methods: In vivo microdialysis and high-performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK-801 treatment. Locomotor activity was measured using a computed video tracking system., Results: Intermittent subchronic MK-801 administration, followed by a 24-h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK-801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice-daily subchronic NMDAR antagonist treatment., Conclusion: These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Aim: Interview quality is an important factor in the success of clinical trials for major depressive disorder (MDD). There is a substantial need to establish a reliable, remote clinical assessment interview system that can replace traditional in-person interviews., Methods: We conducted a multicenter, randomized, unblinded, prospective, cross-sectional study to assess the reliability of remote interviews in patients with MDD (UMIN000041839). Eligible patients with MDD underwent remote and in-person sessions of the Montgomery-Åsberg Depression Rating Scale (MADRS) assessment performed by different raters within 28 days of providing consent. Patients were randomized to a group first assessed using in-person interviews and secondarily using remote interviews (in-person-first group) or a group first assessed by remote interviews and secondarily using in-person interviews (remote-first group). Nineteen trained people (15 clinical psychologists, 3 nurses, and 1 clinical laboratory technologist) performed interviews., Results: Of 59 patients (in-person-first group, n = 32; remote-first group, n = 27) who completed both remote and in-person interviews, 51% (n = 30) were women; the mean age was 41.6 years (range, 21-64 years). There was a strong association between remote and in-person MADRS scores (r = 0.891, kappa = 0.901). An overall intraclass correlation coefficient (ICC) of 0.886 (95% confidence interval, 0.877-0.952) indicated good consistency between MADRS scores in remote and in-person interviews. The ICC decreased as the severity of depression increased., Conclusion: Our results suggest remote interviews are a feasible alternative option to in-person interviews in assessing symptom severity in MDD patients and could promote clinical trials in Japan., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Aim: Impairments in emotional memory are frequently observed in several mental disorders, highlighting their significance as potential therapeutic targets. Recent research on the cued fear conditioning model has elucidated the neural circuits involved in fear memory processing. However, contradictory findings have been reported concerning the role of dopamine and the impact of dopamine D2 receptor (D2R) antagonists. There is notably limited knowledge regarding the clinical utility of chronic D2R antagonist treatments. This study aimed to uncover how such treatments affect fear memory processing., Methods: We utilized a cued fear conditioning rat model and conducted chronic haloperidol treatment for 14 days. Subsequently, to investigate the effect of chronic haloperidol treatment on fear-conditioned memory expression and extinction, we observed freezing behavior under exposure to a conditioned stimulus for 14 days., Results: Chronic haloperidol treatment suppressed freezing time on the fear memory expression. In contrast, a single haloperidol administration enhanced the freezing time on fear memory expression and delayed extinction., Conclusion: The results of this study suggest that chronic administration of antipsychotic drugs affects fear memory processing differently from single-dose administration. This indicates that the effects of chronic D2R antagonist treatment are distinct from the nonspecific effects of the drugs. This study provides fundamental insights that may contribute to our understanding of therapeutic mechanisms for fear memory disorders related to D2R in the future., (© 2024 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10 -8 , odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1., (© 2022. The Author(s).)

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.