Search

Hidenori Maruyama,1 Fumiya Sano,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Itaru Miura5 1Medical Science, Sumitomo Pharma Co., Ltd, Osaka, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Department of Neuropsychiatry, Fukushima Medical University, Fukushima, JapanCorrespondence: Hidenori Maruyama, Tel +81-80-4368-2576, Fax +81-6-6203-5733, Email hidenori.maruyama@sumitomo-pharma.co.jpPurpose: To evaluate the effect of lurasidone on a new, patient Life Engagement scale in schizophrenia.Patients and Methods: This post-hoc analysis included participants (ages 18 to 74) diagnosed with schizophrenia who were randomized to lurasidone (40 mg/day) or placebo in a 6-week double-blind efficacy study and those who continued in a subsequent 12-week open-label extension study during which patients received either 40 or 80/mg day lurasidone (flexibly dosed). Change in life engagement was measured using the Positive and Negative Syndrome Scale (PANSS) 11-item Life Engagement subscale score, and individual subscale items, at week 6 during the double-blind phase and extension phase week 12 during the open-label extension phase.Results: Analysis focused on 478 subjects randomized to lurasidone or placebo during the 6-week trial, and 146 who received lurasidone during the extension phase. During the 6-week trial, there was a significantly greater change on the PANSS11 Life Engagement subscale score from baseline to week 6 in the lurasidone group compared to the placebo group (mean changes of − 6.4 and − 4.8, respectively, p = 0.006; effect size = 0.27). Further improvement was evident during the extension phase for patients who received lurasidone in both phases, with a mean change from double-blind baseline to week 12 of the open-label treatment phase of − 10.1 on in PANSS11 Life Engagement subscale.Conclusion: This post-hoc analysis suggests that lurasidone may improve life engagement in patients with schizophrenia, a meaningful outcome from patients’ perspective. Further studies are needed to confirm this effect.Eudract Number: Trial registration: EudraCT Numbers: 2016-000060-42; 2016-000061-23.Keywords: lurasidone, schizophrenia, antipsychotic agents, life engagement, efficacy

Itaru Miura,1 Sho Horikoshi,1,2 Mizue Ichinose,1,3 Yuhei Suzuki,1 Kenya Watanabe4 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 3Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 4Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpAbstract: This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.Keywords: schizophrenia, lurasidone, serotonin-dopamine antagonist, antipsychotics

Itaru Miura,1 Kei Watabe,2 Reiko Sakaguchi,3 Keisuke Okamoto,4 Hidenori Maruyama5 1Department of Neuropsychiatry, Fukushima Medical University, Fukushima, Japan; 2Department of Data Science, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 3Department of Clinical Research, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 4Department of Clinical Operation, Drug Development Division, Sumitomo Pharma Co., Ltd, Tokyo, Japan; 5Medical Affairs, Sumitomo Pharma Co., Ltd, Tokyo, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University 1 Hikarigaoka, Fukushima, 960-1295, Japan, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpPurpose: To evaluate the effectiveness and safety of lurasidone 80 mg/day (versus the 40 mg/day dose) during a 12-week, open-label extension study in patients with an acute exacerbation of schizophrenia who had completed a 6-week double-blind study of lurasidone.Patients and Methods: A total of 289 adult patients with schizophrenia completed the double-blind study and enrolled in the 12-week extension study. Lurasidone was flexibly dosed at 40 or 80 mg/day. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) subscale scores, Clinical Global Impression-Severity Scale (CGI-S), and Calgary Depression Scale for Schizophrenia (CDSS), analyzed based on last observation carried forward (LOCF-endpoint). Safety/tolerability assessments included adverse events, body weight, laboratory tests, and discontinuation due to adverse events.Results: Mean endpoint change was greater for lurasidone in modal doses of 80 mg/d (N=136) vs 40 mg/d (N=153) on the PANSS positive subscale (− 3.0 vs − 2.3), PANSS negative subscale (− 1.9 vs − 1.7), PANSS General Psychopathology subscale (− 5.1 vs − 3.8), the CGI-S score (− 0.5 vs − 0.4), and the CDSS score (− 0.7 vs − 0.1). Discontinuation rates due to adverse events on lurasidone modal 80 mg/d vs 40 mg/d were 4.4% vs 7.2%; and the most common adverse events in the modal 80 mg/d group were nasopharyngitis, 7.4% (vs 4.6% on modal 40 mg/d), constipation, 5.9% (vs 2.0%), and headache, 5.9% (vs 2.0%).Conclusion: In patients with acute schizophrenia treated with lurasidone 40 mg/d, increasing the dose to 80 mg/d was well tolerated, and was associated with greater improvement in PANSS subscale scores compared to continued treatment with a dose of 40 mg/d.Keywords: lurasidone, schizophrenia, extension treatment, dose escalation, effectiveness, safety

Mizue Ichinose,1,2 Itaru Miura,1 Sho Horikoshi,1,3 Shinnosuke Yamamoto,1,4 Keiko Kanno-Nozaki,1 Kenya Watanabe,5 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 3Department of Psychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 4Department of Psychiatry, Fukushima Red Cross Hospital, Fukushima, Japan; 5Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru MiuraDepartment of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, JapanTel +81-24-547-1331Fax +81-24-548-6735Email itaru@fmu.ac.jpObjective: Although switching antipsychotics is a common strategy in the treatment of schizophrenia, caution is needed because of the risk of worsening of psychosis, particularly when switching to a dopamine D2 partial agonist. Homovanillic acid (HVA), a dopamine metabolite, is thought to be a possible indicator of the response to antipsychotics. We examined the effects of switching to brexpiprazole monotherapy from other antipsychotics on plasma HVA levels and side effects during maintenance treatment of schizophrenia.Methods: The antipsychotics of 37 Japanese patients with schizophrenia or schizoaffective disorder were switched to brexpiprazole for the improvement of side effects. We evaluated clinical symptoms and extrapyramidal symptoms (EPS) and took fasting blood samples at baseline and endpoint (eight weeks after completing the switch) to measure plasma levels of HVA, prolactin, and metabolic parameters.Results: Switching to brexpiprazole significantly decreased the Drug-Induced Extrapyramidal Symptoms Scale total score (p=0.008), prolactin levels (p< 0.001), body weight (p=0.046), and body-mass index (p=0.034), and increased HDL cholesterol (p=0.008). On the other hand, switching to brexpiprazole did not change plasma levels of HVA or Positive and Negative Syndrome Scale scores.Conclusion: Switching to brexpiprazole significantly improved EPS, high prolactin levels, and metabolic side effects without elevating plasma HVA levels. Brexpiprazole may stabilize dopaminergic neural transmission and could be a useful strategy to decrease the burden in patients with schizophrenia during the maintenance phase. Because of the small sample size, further studies with larger sample sizes are needed to confirm and extend our results.Keywords: brexpiprazole, extrapyramidal symptoms, EPS, homovanillic acid, prolactin, schizophrenia, switching

Masashi Ito,1 Yasuto Kunii,1,2 Sho Horikoshi,1 Itaru Miura,1 Shuntaro Itagaki,1 Tetsuya Shiga,1 Hirooki Yabe11Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Fukushima Medical University School of Aizu Medical Center, Fukushima, JapanObjectives: Although clozapine is considered the only effective pharmacological option for patients with treatment-resistant schizophrenia (TRS), around 30–40% of patients show clozapine resistance. Modified electroconvulsive therapy augmentation is reportedly clinically effective for clozapine-resistant schizophrenia, but few case reports have described the efficacy of combining clozapine and continuous/maintenance ECT for patients with TRS.Methods: We present the case of a young patient with TRS who was treated using combination therapy with clozapine and maintenance ECT (m-ECT).Results: The patient achieved drastic improvement under combination therapy with clozapine and m-ECT. Total Positive and Negative Syndrome Scale (PANSS) score fell markedly by 36 (from 108 to 72) using the combination of clozapine and m-ECT. Behaviors not reflected directly by PANSS score also improved. For example, the problem of being unable to take oral drugs stably because of delusions of poisoning was resolved. Furthermore, the patient maintained improvement under m-ECT, and long-term homestays became possible.Conclusion: Combination therapy with clozapine and m-ECT proved greatly effective in this case. Further clinical trials of this combination therapy for TRS are needed to confirm the effectiveness. Further studies are also expected to examine effective periods for this therapy.Keywords: treatment-resistant schizophrenia (TRS), modified electroconvulsive therapy, augmentation, clozapine, maintenance ECT(m-ECT)

Haruka Kaneko,1,2 Itaru Miura,1 Keiko Kanno-Nozaki,1 Sho Horikoshi,1 Mizuki Hino,1 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Hoshi General Hospital, Fukushima, Japan Introduction: The COMT Val 108/158 Met polymorphism (rs4680) may affect treatment response to antipsychotics, as well as metabolism and dynamics of neurotransmitters during the treatment of schizophrenia. We investigated the effects of the COMT Val 108/158 Met polymorphism on treatment response to aripiprazole and plasma monoamine metabolite levels in patients with acute schizophrenia. Materials and methods: Forty patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured Positive and Negative Syndrome Scale (PANSS) and plasma levels of homovanillic acid (HVA) and plasma MHPG (3-methoxy-4-hydroxyphenethyleneglycol) at baseline and endpoint. The COMT Val 108/158 Met polymorphism was genotyped with the polymerase chain reaction and restriction fragment length polymorphism. Results: There were significant genotype–time interactions on PANSS total and general psychopathology scores, with Met/Met genotype showing greater improvement. The response rate to aripiprazole did not differ between COMT Val 108/158 Met genotype groups. We found a significant time effect on plasma MHPG levels, but no time effect on plasma HVA levels or time–genotype interactions in the plasma levels of HVA and MHPG. Although the responder rate did not differ among the 3 genotype groups. Conclusion: Our results suggest that individuals with the Met/Met genotype had greater improvement in PANSS score after the treatment with aripiprazole. On the other hand, the Val 108/158 Met polymorphism may not induce changes in plasma levels of monoamine metabolites during aripiprazole treatment. Because of the small sample size, further studies are needed to confirm and to extend our results. Keywords: schizophrenia, COMT, Val 108/158 Met polymorphism (rs4680), aripiprazole, pharmacogenetics

Satoko Asano, Yasuto Kunii, Hiroshi Hoshino, Yusuke Osakabe, Tetsuya Shiga, Shuntaro Itagaki, Itaru Miura, Hirooki Yabe Department of Neuropsychiatry, School of Medicine Fukushima Medical University, Fukushima, Japan Aim: Delirium is commonly encountered in daily clinical practice. To identify predictors influencing outcomes, we retrospectively examined the characteristics of inpatients with delirium who required psychiatric medication during hospitalization.Methods: We extracted all new inpatients (n=523) consulted for psychiatric symptoms at Fukushima Medical University Hospital between October 2011 and September 2013. We selected 203 inpatients with delirium diagnosed by psychiatrists. We analyzed data from 177 inpatients with delirium who received psychiatric medication. We defined an “early improvement group” in which delirium resolved in ≤3 days after starting psychiatric medication, and a “prolonged group” with delirium lasting for >3 days. Among the 83 inpatients with renal dysfunction (estimated glomerular filtration rate 3 days. We then examined differences between groups for different categorical variables.Results: Dose of antipsychotic medication at end point was significantly lower in the prolonged group with renal dysfunction than in the early improvement group with renal dysfunction.Conclusion: The results suggest that maintaining a sufficient dose of antipsychotics from an early stage may prevent prolongation of delirium even in inpatients with renal dysfunction. Keywords: antipsychotic, prolonged delirium, chronic kidney disease, pharmacokinetics

Sho Horikoshi,1,2 Itaru Miura,2 Yasuto Kunii,3 Satoko Asano,4 Keiko Kanno-Nozaki,2 Hirobumi Mashiko,5 Hirooki Yabe2 1Department of Neuropsychiatry, Hoshi General Hospital, 2Department of Neuropsychiatry, Fukushima Medical University School of Medicine, 3Department of Neuropsychiatry, Fukushima Medical University School of Aizu Medical Center, 4Department of Neuropsychiatry, Japan Red Cross Fukushima Hospital, 5Department of Neuropsychiatry, Fukushima Prefectural General Rehabilitation Center, Fukushima, Japan Abstract: Hashimoto encephalopathy (HE) is believed to be an immune-mediated disorder associated with Hashimoto’s thyroiditis. It was suggested that neuropsychiatric symptoms, the presence of antithyroid antibody, and good response to steroids were important for the diagnosis of HE. It has been reported that homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), which are monoamine metabolites of dopamine and noradrenaline, respectively, are the possible biomarkers of neuropsychiatric diseases. We report a case of Hashimoto encephalopathy, in which we longitudinally measured the plasma levels of monoamine metabolites. A 52-year-old woman developed acute psychosis, and was admitted to the psychiatric ward of our hospital due to psychotic state, 6 days after a traffic accident. An extensive evaluation showed no remarkable findings, except an increase in antithyroglobulin antibodies. Plasma levels of HVA and MHPG were extremely high at 66.5 and 41.8 ng/mL, respectively. On day 16, 50 mg/day oral prednisolone was administered, which improved her psychotic symptoms. Plasma levels of HVA and MHPG decreased to 7.2 and 9.9 ng/mL, respectively, on day 19. After the temporary worsening of psychosis and increase in plasma levels of HVA and MHPG, the dosage of prednisolone was tapered and low-dose risperidone was started. Her psychiatric symptoms gradually improved and plasma monoamine metabolite levels decreased again (HVA: 17.9 ng/mL; MHPG: 7.7 ng/mL). Although autoimmune mechanism has been suggested to be involved in HE, neural mechanism and pathogenesis of HE remain unknown. Our findings suggest that monoaminergic neural activity might be associated with psychotic symptoms in patients with HE and plasma levels of monoamine metabolites might be useful as state markers. Keywords: Hashimoto encephalopathy, monoamine metabolite, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, symptomatic psychosis

Two different types of sex chromosomes, XX/XY and ZZ/ZW, exist in the Japanese frog Rana rugosa. They are separated in two local forms that share a common origin in hybridization between the other two forms (West Japan and Kanto) with male heterogametic sex determination and homomorphic sex chromosomes. In this study, to find out how the different types of sex chromosomes differentiated, particularly the evolutionary reason for the heterogametic sex change from male to female, we performed artificial crossings between the West Japan and Kanto forms and mitochondrial 12S rRNA gene sequence analysis. The crossing results showed male bias using mother frogs with West Japan cytoplasm and female bias using those with Kanto cytoplasm. The mitochondrial genes of ZZ/ZW and XX/XY forms, respectively, were similar in sequence to those of the West Japan and Kanto forms. These results suggest that in the primary ZZ/ZW form, the West Japan strain was maternal and thus male bias was caused by the introgression of the Kanto strain while in the primary XX/XY form and vice versa. We therefore hypothesize that sex ratio bias according to the maternal origin of the hybrid population was a trigger for the sex chromosome differentiation and the change of heterogametic sex.

A study to determine the evolutionary reasons for and mechanisms of heterogametic sex change is conducted in order to understand the evolutionary mechanisms of sex determination. There are two main types of heterogamety, male heterogamety (XX/XY) and female heterogamety (ZZ/ZW).