Association between TNF-α & IL-6 level changes and remission from depression with duloxetine treatment.

PURPOSE/AIM OF THE STUDY: The pathophysiology of major depressive disorder (MDD) involves multiple factors, including inflammatory processes. This study investigated the relationship between changes in the levels of cytokines and remission in patients with MDD following duloxetine treatment. MATERIALS AND METHODS: MDD patients were administered duloxetine for 16 weeks. Clinical evaluation and immunological monitoring were performed every 4 weeks. RESULTS: Our results indicated that changes in serum levels of TNF-α and IL-6 were associated with remission following duloxetine treatment in MDD patients. There was a slight increase in TNF-α levels in the first four weeks following duloxetine treatment, which correlated significantly with patients who were in remission. Furthermore, patients in remission exhibited an initial increase in IL-6 levels in the first four weeks, followed by a decrease at 16 weeks. CONCLUSIONS: These results suggest an important relationship between changes in cytokine levels and remission in patients with major depression after duloxetine treatment.

Randomized open-label study of second-generation antipsychotics for the treatment of schizophrenia: 104-week final results of the JUMPs study assessing treatment discontinuation, remission, and social functioning.

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).

Several supplementary concepts for applied category-theoretical states over an extended Petri net using an example relating to genetic coding: Toward an abstract algebraic formulation of molecular/genetic biology.

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×Z2ׅ' 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.

Effect of intermittent subchronic MK-801 administration on dopamine synthesis capacity and responsiveness in the prefrontal cortex.

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.

Effects of chronic haloperidol treatment on the expression of fear memory and fear memory extinction in the cued fear-conditioned rats.

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.

Feasibility of remote interviews in assessing disease severity in patients with major depressive disorder: A pilot study.

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.

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

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.

Efficacy and Safety of Blonanserin Oral Tablet in Adolescents with Schizophrenia: A 6-Week, Randomized Placebo-Controlled Study.

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.

Discontinuation and remission rates and social functioning in patients with schizophrenia receiving second-generation antipsychotics: 52-week evaluation of JUMPs, a randomized, open-label study.

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.

Long-Term Safety and Efficacy of Blonanserin Oral Tablet in Adolescents with Schizophrenia: A 52-Week, Multicenter, Open-Label Extension Study.

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.

Patient and Physician Perspectives of Depressive Symptoms and Expectations for Treatment Outcome: Results from a Web-Based Survey.

PURPOSE: 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.

Lurasidone in the long-term treatment of Japanese patients with bipolar I disorder: a 52 week open label study.

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.

Safety and Effectiveness of Lurasidone in Patients with Schizophrenia: A 12-Week, Open-Label Extension Study.

PURPOSE: 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.

Efficacy and safety of lurasidone in acutely psychotic patients with schizophrenia: A 6-week, randomized, double-blind, placebo-controlled study.

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.

Safety of switching to brexpiprazole in Japanese patients with schizophrenia: A post-hoc analysis of a long-term open-label study.

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.

Dual orexin receptor antagonist (DORA-12) treatment affects the overall levels of Net/maoA mRNA expression in the hippocampus.

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.

Lurasidone in the Long-Term Treatment of Bipolar I Depression: A 28-week Open Label Extension Study.

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.

Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire.

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.