Publications by authors named "Yasunori Oda"

59 Publications

An Increase in the Levels of Middle Surface Antigen Characterizes Patients Developing HBV-Driven Liver Cancer Despite Prolonged Virological Suppression.

Microorganisms 2021 Apr 2;9(4). Epub 2021 Apr 2.

Department of Experimental Medicine, Tor Vergata University, 00133 Rome, Italy.

Hepatitis B virus (HBV) contains three surface glycoproteins-Large-HBs (L-HBs), Middle-HBs (M-HBs), and Small-HBs (S-HBs), known to contribute to HBV-driven pro-oncogenic properties. Here, we examined the kinetics of HBs-isoforms in virologically-suppressed patients who developed or did not develop hepatocellular carcinoma (HCC). This study enrolled 30 chronically HBV-infected cirrhotic patients under fully-suppressive anti-HBV treatment. Among them, 13 patients developed HCC. Serum samples were collected at enrolment (T0) and at HCC diagnosis or at the last control for non-HCC patients (median (range) follow-up: 38 (12-48) months). Ad-hoc ELISAs were designed to quantify L-HBs, M-HBs and S-HBs (Beacle). At T0, median (IQR) levels of S-HBs, M-HBs and L-HBs were 3140 (457-6995), 220 (31-433) and 0.2 (0-1.7) ng/mL. No significant differences in the fraction of the three HBs-isoforms were noticed between patients who developed or did not develop HCC at T0. On treatment, S-HBs showed a >25% decline or remained stable in a similar proportion of HCC and non-HCC patients (58.3% of HCC- vs. 47.1% of non-HCC patients, = 0.6; 25% of HCC vs. 29.4% of non-HCC, = 0.8, respectively). Conversely, M-HBs showed a >25% increase in a higher proportion of HCC compared to non-HCC patients (50% vs. 11.8%, = 0.02), in line with M-HBs pro-oncogenic role reported in in vitro studies. No difference in L-HBs kinetics was observed in HCC and non-HCC patients. In conclusion, an increase in M-HBs levels characterizes a significant fraction of HCC-patients while under prolonged HBV suppression and stable/reduced total-HBs. The role of M-HBs kinetics in identifying patients at higher HCC risk deserves further investigation.
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http://dx.doi.org/10.3390/microorganisms9040752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065957PMC
April 2021

Oxytocin system dysfunction in patients with treatment-resistant schizophrenia: Alterations of blood oxytocin levels and effect of a genetic variant of OXTR.

J Psychiatr Res 2021 Mar 30;138:219-227. Epub 2021 Mar 30.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.

Treatment-resistant schizophrenia (TRS) has a quite complex pathophysiology that includes not only severe positive symptoms but also other symptom domains. Much attention has been devoted to the overlapping psychological and biological profiles of schizophrenia and autistic spectrum disorder (ASD). We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on general cognitive and social cognitive impairment and oxytocin system dysfunction. Our analyses revealed that there was no difference in oxytocin concentration among the three groups. The TRS patients' oxytocin blood concentrations were positively correlated with their processing speed and theory-of-mind scores, whereas the RemSZ and ASD groups had no significant relation with any measures. Rs53576, a single nucleotide polymorphism on the oxytocin receptor gene, affected social cognition abilities in the schizophrenia group. Although the overall findings are preliminary, they indicate that oxytocin system dysfunction could be involved in the serious cognitive deficits in TRS patients. Further, these results suggest that patients with TRS might have early neurodevelopmental abnormalities based on their shared biological features with ASD patients.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.053DOI Listing
March 2021

Recent discussions on dopamine supersensitivity psychosis: Eight points to consider when diagnosing treatment-resistant schizophrenia.

Curr Neuropharmacol 2021 Jan 25. Epub 2021 Jan 25.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba. Japan.

Dopamine supersensitivity psychosis is a clinical concept characterized by an unstable psychotic state and tardive dyskinesia in schizophrenia patients at the chronic stage. This state is thought to be induced by a compensatory upregulation of dopamine D2 receptors, which is provoked by long-term and/or high-dose medications. Recent clinical data suggest that patients who responded well to medication but later exhibit dopamine supersensitivity develop tolerance to antipsychotics' effects and eventually transit to treatment-resistant schizophrenia, indicating that dopamine supersensitivity could be an etiology contributing to treatment-resistant schizophrenia. However, any clinicians and researchers consider dopamine supersensitivity psychosis a minor phenomenon during the clinical course and do not make much of it. This opinion is often based on numerous clinical data which indicating that dopamine supersensitivity psychosis is a relatively rare event. This review examines the data dealing with dopamine supersensitivity with the five themes of frequency, severity, withdrawal studies, switching to aripiprazole, and tardive dyskinesia. These themes' effects on discussions of the clinical meaning of dopamine supersensitivity psychosis are then reviewed. The present review will help clinicians to speculate as to the background of severe psychopathology in a given patient; to make diagnoses of treatment-resistant schizophrenia and dopamine supersensitivity psychosis; and to plan antipsychotic medication regimens with the goal of achieving better long-term prognosis.
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http://dx.doi.org/10.2174/1570159X19666210125152815DOI Listing
January 2021

Reduction of dopamine and glycogen synthase kinase-3 signaling in rat striatum after continuous administration of haloperidol.

Pharmacol Biochem Behav 2021 Mar 22;202:173114. Epub 2021 Jan 22.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan.

Background: Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats.

Methods: Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions.

Results: In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/β and an increase in the pGSK-3β/GSK-3β ratio, whereas AKT was not changed.

Conclusions: Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS.
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http://dx.doi.org/10.1016/j.pbb.2021.173114DOI Listing
March 2021

Effects of repeated electroconvulsive shocks on dopamine supersensitivity psychosis model rats.

Schizophr Res 2021 Feb 8;228:1-6. Epub 2021 Jan 8.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan.

While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.
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http://dx.doi.org/10.1016/j.schres.2020.11.062DOI Listing
February 2021

Association between serum levels of glial cell line-derived neurotrophic factor and inattention in adult patients with attention deficits/hyperactivity disorder.

Psychiatry Res 2021 Feb 29;296:113674. Epub 2020 Dec 29.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Child Psychiatry, Chiba University Hospital, Chiba, Japan; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Glial cell line-derived neurotrophic factor (GDNF) may play an important role in attention. We investigated the association between serum GDNF levels and clinical status in unmedicated adults with attention deficit/hyperactivity disorder (ADHD) (n = 16) and healthy controls (n = 33); the levels were comparable between the ADHD and control groups (107.2 ± 31.7 vs. 110.5 ± 40.0 pg/mL, respectively; p = 0.77). In the ADHD group, higher GDNF serum levels were associated with severe subjective inattention (r = 0.528, p = 0.035). These preliminary results suggest that the serum GDNF level may not be a suitable biomarker for adult ADHD, although it may be associated with the pathophysiology of persistent inattention in adult ADHD.
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http://dx.doi.org/10.1016/j.psychres.2020.113674DOI Listing
February 2021

Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder.

J Psychiatr Res 2021 02 21;134:48-56. Epub 2020 Dec 21.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address:

Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.
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http://dx.doi.org/10.1016/j.jpsychires.2020.12.051DOI Listing
February 2021

Astroglial glutamate transporter 1 and glutamine synthetase of the nucleus accumbens are involved in the antidepressant-like effects of allopregnanolone in learned helplessness rats.

Behav Brain Res 2021 03 28;401:113092. Epub 2020 Dec 28.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuou-ku, Chiba, Chiba, 260-8670, Japan.

Clinical studies have demonstrated that allopregnanolone (3α5α-tetrahydroprogesterone, ALLO) has antidepressant-like effects on patients with depression. Previous studies have shown alteration of the astroglial glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) in depression, and ALLO is known to modulate glutamate release. The present study aimed to investigate whether astroglial GLT-1 and GS are indeed involved in the antidepressant-like effects of ALLO in learned helplessness (LH) rats, a validated animal model of depression. The results of this study showed that bilateral microinjection of ALLO into the lateral ventricles could normalize the levels of GLT-1 and GS in the nucleus accumbens (NAc) and of GS in the hippocampal CA1 region of LH rats. These results suggest a certain connection between the antidepressant-like effects of ALLO and the astroglial GLT-1/GS system of the NAc in LH rats.
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http://dx.doi.org/10.1016/j.bbr.2020.113092DOI Listing
March 2021

A randomized-controlled trial of blonanserin and olanzapine as adjunct to antipsychotics in the treatment of patients with schizophrenia and dopamine supersensitivity psychosis: The ROADS study.

Asian J Psychiatr 2020 Oct 31;53:102369. Epub 2020 Aug 31.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Child Psychiatry, Chiba University Hospital, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan.

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.
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http://dx.doi.org/10.1016/j.ajp.2020.102369DOI Listing
October 2020

Prussian blue in salt blocks decreases radiocesium activity concentration in milk from dairy cattle fed a diet contaminated by the Fukushima nuclear accident.

J Environ Radioact 2020 Oct 9;222:106307. Epub 2020 Jul 9.

Department of Life Science and Agriculture, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan. Electronic address:

In Japan, the radiocesium activity concentration in milk must be less than 50 Bq/kg-fresh to meet shipping standards, and the radiocesium concentration of the diet fed to dairy cattle must be less than 500 Bq/kg-dry. After the Fukushima nuclear accident in 2011, we conducted two experiments to investigate whether Prussian blue (PB) could suppress the radiocesium (Cs + Cs) activity concentration in Japanese cattle' milk. In experiment 1, four cattle were fed a diet with a radiocesium activity concentration of 175 Bq/kg-dry, with or without PB supplementation. The PB intake ranged from 0 to 3.0 g/day, and the average radiocesium intake was 3.42 kBq/day in all treatments. The radiocesium activity concentration in milk decreased from 16.4 to 8.6 Bq/kg-fresh, and the transfer coefficient of radiocesium from diet to milk (Fm) decreased from 4.77 × 10 to 2.61 × 10 with increased PB intake. In experiment 2, three cattle were fed another diet including a radiocesium activity concentration of 927 Bq/kg-dry of with or without PB supplementation. The PB intake ranged from 0 to 18.9 g/day, and the average radiocesium intake was 15.2 kBq/day in all treatments. The milk's radiocesium activity concentration decreased from 24.3 to 4.2 Bq/kg-fresh, and the Fm decreased from 1.68 × 10 to 0.28 × 10 with increased PB intake. Our results suggest that both the radiocesium activity concentration in milk and Fm can be reduced by PB, and that Fm is affected by diet. We recommend cattle should be fed absorbents such as PB to minimize the risk of milk radiocesium activity concentration exceeding 50 Bq/kg-fresh even if the diet has a radiocesium activity concentration of less than 500 Bq/kg-dry.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106307DOI Listing
October 2020

Autistic traits and cognitive profiles of treatment-resistant schizophrenia.

Schizophr Res Cogn 2020 Dec 27;22:100186. Epub 2020 Jul 27.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.

The complex pathophysiology of treatment-resistant schizophrenia (TRS) includes severe positive symptoms but also other symptom domains. The overlapping psychological profiles of schizophrenia and autistic spectrum disorder (ASD) are not established. We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on both neurodevelopmental aspects and general and social cognitive impairments. The TRS group performed the worst on general neurocognition (measured by the MATRICS Consensus Cognitive Battery) and social cognition (measured by the theory of mind and emotional expression). The RemSZ group performed the best among the three groups. Regarding autistic traits, all measurements by the Autism-Spectrum Quotient/Autism Screening Questionnaire/Pervasive Developmental Disorder Assessment Rating Scale showed that (1) the ASD patients had the highest autistic traits (2) the TRS patients' scores were less severe than the ASD group's, but (3) the overall trends placed the TRS group between the ASD and the RemSZ group. These findings indicate that TRS patients and remitted patients could have distinctive neurodevelopmental and cognitive profiles. Further, the degrees of social cognitive dysfunction and autistic traits in TRS patients could be close to those of ASD patients, suggesting similarities between TRS and ASD.
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http://dx.doi.org/10.1016/j.scog.2020.100186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390750PMC
December 2020

Successful rechallenge with paliperidone after clozapine treatment for a patient with dopamine supersensitivity psychosis.

SAGE Open Med Case Rep 2020 7;8:2050313X20929561. Epub 2020 Jun 7.

Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan.

We describe the case of a 49-year-old Japanese male patient successfully treated with a paliperidone rechallenge following 2-year treatment with clozapine for treatment-resistant schizophrenia. He had responded well to conventional antipsychotic treatment for the initial psychotic episode but gradually developed dopamine supersensitivity; even treatment with paliperidone and another antipsychotic medication (a total up to 1700 mg in chlorpromazine-equivalent dose) had not improved his psychotic symptoms. Clozapine treatment produced temporary symptomatic relief, but the clozapine dose could not be increased to > 150 mg due to the patient's intolerance. Following low-dose clozapine treatment for 2 years, a rechallenge with paliperidone monotherapy ameliorated his psychotic symptoms. This suggests that clozapine may have the potential to release the dopamine supersensitivity state. Our patient's case indicates that for patients with dopamine supersensitivity psychosis, a rechallenge with a previously ineffective antipsychotic after clozapine treatment may be successful.
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http://dx.doi.org/10.1177/2050313X20929561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278325PMC
June 2020

The alterations of glutamate transporter 1 and glutamine synthetase in the rat brain of a learned helplessness model of depression.

Psychopharmacology (Berl) 2020 Aug 22;237(8):2547-2553. Epub 2020 May 22.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuou-ku, Chiba, Chiba, 260-8670, Japan.

Background: Although glutamate transmission via astrocytes has been proposed to contribute to the pathophysiology of depression, the precise mechanisms are unknown. Herein, we investigated the levels of glutamate transporter-1 (GLT-1) and glutamine synthetase (GS) of astrocytes in learned helplessness (LH) rats (an animal model of depression) and non-LH rats (an animal model of resilience).

Methods: We administered inescapable mild electric shock to rats and then discriminated the LH and non-LH rats by a post-shock test. Almost 55% of the rats acquired LH. We then measured the expressions of GLT-1 and GS in several brain regions of LH and non-LH rats by Western blot analysis.

Results: The levels of GLT-1 and GS in the CA-1, CA-3, dentate gyrus (DG), medial prefrontal cortex (mPF), and nucleus accumbens (NAc) of the LH group were significantly higher than those of the control group. The GS levels in the amygdala of the LH rats were significantly decreased compared to the controls. There were significant differences in GLT-1 and GS levels between the non-LH and LH rats in the CA-1 and CA-3.

Conclusions: These results suggest that the LH rats experienced up-regulations of GLT-1 and GS in the CA-1, CA-3, DG, mPF, and NAc and a down-regulation of GS in the amygdala. It is possible that the effects of the GLT-1 and GS levels on astrocytes in the CA-1 and CA-3 are critical for the differentiation of resilience from vulnerability.
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http://dx.doi.org/10.1007/s00213-020-05555-3DOI Listing
August 2020

Allopregnanolone induces antidepressant-like effects through BDNF-TrkB signaling independent from AMPA receptor activation in a rat learned helplessness model of depression.

Behav Brain Res 2020 07 11;390:112670. Epub 2020 May 11.

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Allopregnanolone (ALLO, 3α5α-tetrahydroprogesterone) was found to be effective for depressed patients. Animal models of depression indicate that ALLO is associated with the pathophysiology of depression. Traditional antidepressant drugs produce antidepressant effects via the monoamine system, with consequent up-regulation of brain-derived neurotrophic factor (BDNF). This study was designed to examine whether the antidepressant effects of ALLO involve BDNF-TrkB signaling or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation on the learned helplessness paradigm. The antidepressant-like effect of ALLO infusion into the cerebral ventricle was blocked by coinfusion of TrkB inhibitor ANA-12, but not by co-administration of AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX). Thus, the antidepressant-like effect of ALLO involves BDNF signaling independent from AMPA receptor activation.
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http://dx.doi.org/10.1016/j.bbr.2020.112670DOI Listing
July 2020

Monoaminergic balances predict non-depression-like phenotype in Learned Helplessness Paradigm.

Neuroscience 2020 08 25;440:290-298. Epub 2020 Mar 25.

Department of Psychiatry, Teikyo University Chiba Medical Center, Ichihara, Japan; Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Electronic address:

Monoamine neuronal system abnormality is hypothesized to be the neurochemical pathology in depression, as it is supported by the efficacy of conventional antidepressants. The learned helplessness paradigm generates depression-like (LH) and non-depression-like (non-LH) behavioral models. Examination of the neurochemical states accompanying such distinct behavioral phenotypes can facilitate investigations of the mechanisms underlying resilience and the search for new strategies for depression prevention and therapy. Here, we measured the levels of monoamines, including noradrenaline (NA), serotonin (5-HT), and dopamine (DA), and their metabolites in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), hippocampus, nucleus accumbens (NAc), amygdala, and striatum in LH, non-LH, and non-manipulated (naïve) rats. Compared with LH rats, non-LH rats showed lower 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and NA turnovers in the amygdala and higher 5-HT levels in the NAc. Compared with naïve rats, non-LH rats showed increased DA and homovanillic acid (HVA) levels in the amygdala and increased 5-hydroxyindoleacetic acid (5-HIAA) levels in the hippocampus and NAc, whereas LH rats exhibited increased HVA levels and DA turnovers in the hippocampus, decreased 5-HIAA levels in the mPFC, increased DA turnovers in the OFC, and decreased DA turnovers in the amygdala. Comparison between LH and non-LH suggest that suppressed amygdaloid NA activity and elevated 5-HT activity in the NAc are related to stress resilience. Changes that occurred in LH or non-LH rats when compared with those in naïve rats suggest that suppressed DA activity in the hippocampus and OFC; elevated DA activity in the amygdala; and facilitated 5-HT activity in the hippocampus, mPFC, and NAc are phenomena related to the expression of a non-depression-like phenotype.
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http://dx.doi.org/10.1016/j.neuroscience.2020.03.033DOI Listing
August 2020

Metabolism of risperidone by CYP2D6 and the presence of drug-induced dopamine supersensitivity psychosis in patients with schizophrenia.

Int Clin Psychopharmacol 2019 05;34(3):124-130

Department of Psychiatry, Chiba University Graduate School of Medicine.

High-dose antipsychotic(s) can induce dopamine supersensitivity psychosis in schizophrenia patients. The precise relationship between a drug's blood concentration and the occurrence of dopamine supersensitivity psychosis has not been established. We divided 36 patients with schizophrenia who had undergone treatment mainly with risperidone into two groups: one with normal metabolizing activity of CYP2D6 (n = 15), and the other with lower activity of its variant, CYP2D6*10 (n = 21). The patients' blood concentrations of risperidone and 9-OH-risperidone were measured, and we compared the occurrence of dopamine supersensitivity psychosis episodes between the groups. There was no significant difference in any concentration of risperidone, 9-OH-risperidone, or active moiety between the groups although the with-CYP2D6*10 group had greater variabilities of these parameters compared to the without-CYP2D6*10 group. There was a lower rate of dopamine supersensitivity psychosis episodes in the without-CYP2D6*10 group (4/15, 26.7%) compared to the with-CYP2D6*10 group (11/21, 52.4%), but the difference was not significant. Although our findings were negative, largely because of the small sample size, these results suggest that (1) patients with an impaired functional allele of CYP2D6 may have higher concentrations of risperidone and its active metabolite and that (2) these patients may experience more frequent dopamine supersensitivity psychosis episodes.
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http://dx.doi.org/10.1097/YIC.0000000000000257DOI Listing
May 2019

Vulnerable combinations of functional dopaminergic polymorphisms to late-onset treatment resistant schizophrenia.

PLoS One 2018 8;13(11):e0207133. Epub 2018 Nov 8.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chuou-ku, Chiba, Chiba, Japan.

Background: A significant portion of patients with schizophrenia who respond to initial antipsychotic treatment acquire treatment resistance. One of the possible pathogeneses of treatment-resistant schizophrenia (TRS) is antipsychotic-induced dopamine supersensitivity psychosis (Ai-DSP). Patients with this disease progression might share some genetic vulnerabilities, and thus determining individuals with higher risks of developing Ai-DSP could contribute to preventing iatrogenic development of TRS. Therefore, we decided to examine whether combinations of functional single nucleotide polymorphisms (SNPs) known to affect dopaminergic functions are related to Ai-DSP development.

Methods: In this case-control study, 357 Japanese participants diagnosed with schizophrenia or schizoaffective disorder were recruited and divided into two groups, those with and without Ai-DSP. As functional SNPs, we examined rs10770141 of the tyrosine hydroxylase gene, rs4680 of the catechol-O-methyltransferase gene, and rs1799732 and rs1800497 of the DRD2 genes, which are known to possess strong directional ties to dopamine synthesis, dopamine degradation and post-synaptic DRD2 prevalence, respectively.

Results: Among the 357 Japanese patients with schizophrenia or schizoaffective disorder, 130 were classified as Ai-DSP(+) and the other 227 as Ai-DSP(-). Significantly higher proportions of Ai-DSP(+) patients were found to have the SNP combinations of rs10770141/rs4680 (57.9%, OR2.654, 95%CI1.036-6.787, P = 0.048) and rs10770141/rs4680/ rs1800497 (64.3%, OR4.230, 95%CI1.306-13.619, P = 0.029). However, no single SNP was associated with Ai-DSP.

Conclusions: We preliminarily found that carrying particular combinations of functional SNPs, which are related to relatively higher dopamine synthesis and dopamine degradation and lower naïve DRD2, might indicate vulnerability to development of Ai-DSP. However, further studies are needed to validate the present results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224074PMC
April 2019

Vascular risk factors and the relationships between cognitive impairment and hypoperfusion in late-onset Alzheimer's disease.

Acta Neuropsychiatr 2018 Dec 22;30(6):350-358. Epub 2018 Aug 22.

1Department of Psychiatry,Teikyo University Chiba Medical Center,Ichihara,Japan.

Objective: Our recent single-photon emission computed tomography (SPECT) study of patients with late-onset Alzheimer's disease (AD) revealed that regional cerebral blood flow (rCBF) was reduced in the frontal, temporal, and limbic lobes, and to a lesser degree in the parietal and occipital lobes. Moreover, these patients' scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were significantly correlated with rCBF in some gyri of the frontal, parietal, and limbic lobes. Our present study aimed to understand how vascular factors and metabolic disease influenced the relationship between rCBF and ADAS-cog scores.

Methods: We divided late-onset AD patients into two groups according to their Hachinski Ischemic Score (HIS), low vascular risk patients had values of ≤4 (n=25) and high vascular risk patients had scores ≥5 (n=15). We examined rCBF using brain perfusion SPECT data.

Results: The degrees and patterns of reduced rCBF were largely similar between late-onset AD patients in both groups, regardless of HIS values. Cognitive function was significantly associated with rCBF among late-onset AD patients with low vascular risk (HIS≤4), but not among those with high vascular risk (HIS≥5). Furthermore, metabolic diseases, such as hypertension and diabetes mellitus, disrupted the relationships between hypoperfusion and cognitive impairments in late-onset AD patients.

Conclusion: Factors other than hypoperfusion, such as hypertension and diabetes mellitus, could be involved in the cognitive dysfunction of late-onset AD patients with high vascular risk.
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http://dx.doi.org/10.1017/neu.2018.17DOI Listing
December 2018

Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol.

Eur J Pharmacol 2018 Jul 22;830:26-32. Epub 2018 Apr 22.

Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan.

Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D, D and serotonin receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D agonist quinpirole-induced hyperlocomotion test and a dopamine D receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D receptor density. Further, our results show that mRNA levels of dopamine D and D receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D receptors than haloperidol, antagonism of blonanserin at dopamine D receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity.
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http://dx.doi.org/10.1016/j.ejphar.2018.04.014DOI Listing
July 2018

rCBF and cognitive impairment changes assessed by SPECT and ADAS-cog in late-onset Alzheimer's disease after 18 months of treatment with the cholinesterase inhibitors donepezil or galantamine.

Brain Imaging Behav 2019 Feb;13(1):75-86

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.

Late-onset Alzheimer's disease (AD) differs substantially from early-onset AD. In this cross sectional study we investigated brain perfusion changes after 18 months of treatment with cholinesterase inhibitors (ChEIs) donepezil or galantamine. Twenty-five drug-naïve late-onset AD patients were recruited from outpatient clinics. We examined brain perfusion using single photon emission computed tomography (SPECT) and used three-dimensional stereotactic surface projection (3D-SSP) and the stereotactic extraction estimation method (SEE) level 3 to analyze classified gyrus level segments. We assessed cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) grouped into three subgroup domains, language, memory, and praxis. In the follow-up data, some regions were further hypoperfused, reflecting worsening of the disease, while other regions showed alleviated hypoperfusion, potentially related to the ChEIs treatment. Regional cerebral blood flow (rCBF) decreased in the parietal cortex and increased in the frontal and the limbic cortices. Increased hypoperfusion significantly correlated with ADAS-cog scores changes were seen in the superior parietal lobule, inferior parietal lobule, angular gyrus, and supramarginal gyrus of the parietal cortex. Alleviated hypoperfusion significantly related to recovery of ADAS-cog scores were seen in the rectal and paracentral lobule of the frontal cortex, and the anterior cingulate of the limbic cortex. These regions showed significant relationships with total ADAS-cog and language, memory and praxis subscales scores. The current longitudinal study indicates prominent rCBF changes and their relationships with changes in ADAS-cog scores in late-onset AD patients.
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http://dx.doi.org/10.1007/s11682-017-9803-yDOI Listing
February 2019

Alterations in glutamatergic signaling in the brain of dopamine supersensitivity psychosis and non-supersensitivity psychosis model rats.

Psychopharmacology (Berl) 2017 Oct 25;234(20):3027-3036. Epub 2017 Jul 25.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan.

Background: The long-term administration of antipsychotics is known to induce dopamine supersensitivity psychosis (DSP). Although the mechanism of DSP involves mainly a compensatory upregulation of dopamine D2 receptors, the precise mechanisms underlying DSP are unknown. It is known that glutamatergic signaling plays a key role in psychosis. We thus conducted this study to investigate whether glutamatergic signaling plays a role in the development of DSP.

Methods: Haloperidol (0.75 mg/kg/day for 14 days) or vehicle was administered to rats via osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSP rats and non-DSP rats based on locomotion data. Tissue levels of glutamate, glutamine, glycine, L-serine, D-serine, and GABA and the protein expressions of N-methyl-D-aspartate receptors (NMDAR), glutamic acid decarboxylase (GAD), and serine hydroxymethyltransferase (SHMT) in the rat brain regions were examined.

Results: In the DSP rats, the ratio of GABA to glutamate was significantly increased. In addition, the ratio of L-serine to glycine was increased. The striatal expressions of GAD and SHMT2 in the DSP rats were significantly increased. In contrast, the striatal expression of NMDAR2B in the non-DSP rats was significantly decreased.

Conclusions: The present study suggests that glutamatergic signaling is relatively decreased to GABA in DSP rats. Our results also showed that excessive doses of haloperidol can induce striatal NMDAR hypofunction in non-DSP rats, which could prevent the formation of tardive dyskinesia but cause treatment resistance. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, further research exploring our present findings is necessary.
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http://dx.doi.org/10.1007/s00213-017-4695-5DOI Listing
October 2017

Relationships between cognitive impairment on ADAS-cog and regional cerebral blood flow using SPECT in late-onset Alzheimer's disease.

J Neural Transm (Vienna) 2017 09 16;124(9):1109-1121. Epub 2017 May 16.

Department of Psychiatry, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, 299-0111, Japan.

The aim of this study was to examine brain hypoperfusion and its relationship with cognitive dysfunction in late-onset Alzheimer's disease (AD). Forty patients with late-onset AD and not receiving acetylcholinesterase inhibitors were recruited from outpatient clinics. We examined cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and brain perfusion using single-photon emission computed tomography, and analyzed classified gyrus level segments with three-dimensional stereotactic surface projection and the stereotactic extraction estimation method level 3. ADAS-cog subscales were grouped into three domains: language, memory, and praxis. Patients with late-onset AD showed an apparent reduction in regional cerebral blood flow (rCBF) with a z score >1.5 in the frontal, temporal, and limbic lobes, with lesser reduction in the parietal and occipital lobes. Although hypoperfusion in the orbital, rectal, and subcallosal gyri of the frontal lobe was prominent, rCBF in the inferior frontal gyrus of the frontal lobe was significantly correlated with ADAS-cog total and language and praxis subscale scores. The parahippocampal gyrus of the limbic lobe was also significantly correlated with the ADAS-cog total, language, and praxis subscale scores. Additionally, the cingulate of the limbic lobe was significantly related with ADAS-cog memory. In spite of lesser hypoperfusion, the posterior cingulate gyrus of the limbic lobe was significantly related with ADAS-cog total, language, and memory subscale scores. Further, each subdivision of ADAS-cog was found to be related with various brain regions.
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http://dx.doi.org/10.1007/s00702-017-1734-7DOI Listing
September 2017

SLC2A1/GLUT1 expression in mural nodules of intraductal papillary mucinous neoplasm of the pancreas.

Hum Pathol 2017 07 12;65:71-78. Epub 2017 Apr 12.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

In intraductal papillary mucinous neoplasms (IPMNs), the presence of a mural nodule showing a papillary or nodular proliferation of tumor cells in the dilated pancreatic duct is an indication for resection of IPMN. Solute carrier family 2, facilitated glucose transporter member 1, known as glucose transporter type 1 (SLC2A1/GLUT1) mediates cellular glucose uptake in many carcinomas and is correlated with increased F-fluorodeoxyglucose (F-FDG) uptake. We examined SLC2A1/GLUT1 expression in the mural nodules of 180 IPMN specimens to distinguish malignant/benign tumors. A mural nodule was detected in 80 (44.4%) of the IPMNs, and was detected in 18.6% (13/70) of the IPMN-low (dysplasia) specimens, 36.1% (13/36) of the IPMN-int, 93.3% (28/30) of the IPMN-high, and 59.1% (26/44) of the IPMN-inv (with an associated invasive carcinoma) specimens. The sensitivity for detecting mural nodules was 81.7% by endoscopic ultrasonography, 70% by contrast-enhanced computed tomography and 54% by endoscopic retrograde cholangiopancreatography. SLC2A1/GLUT1 expression in the mural nodules was recognized in the basal and basolateral cytomembrane of tumor cells and was expressed in 15.4% (2/13) of the IPMN-low, 15.4% (2/13) of the IPMN-int, 71.4% (20/28) of the IPMN-high and 84.6% (22/26) of the IPMN-inv groups. The SLC2A1/GLUT1 expression was significantly higher in the IPMN-high and IPMN-inv mural nodules than in those of the IPMN-low and IPMN-int groups. Our findings suggest that SLC2A1/GLUT1 is expressed late in the adenoma-carcinoma sequence during carcinogenesis in IPMN, and SLC2A1/GLUT1 act as therapeutic target for malignant IPMN.
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http://dx.doi.org/10.1016/j.humpath.2017.03.008DOI Listing
July 2017

Molecular Characteristics of Pancreatic Ductal Adenocarcinomas with High-Grade Pancreatic Intraepithelial Neoplasia (PanIN) Are Different from Those without High-Grade PanIN.

Pathobiology 2017 15;84(4):192-201. Epub 2017 Mar 15.

Department of Anatomic Pathology, Kyushu University, Fukuoka, Japan.

Aims: We reported that pancreatic ductal adenocarcinomas (PDACs) without high-grade pancreatic intraepithelial neoplasia (PanIN) in the vicinity had worse prognoses than PDACs with high-grade PanIN. However, the molecular characteristics of PDACs with and without high-grade PanIN have not been compared. The aim of this study is to clarify the molecular characteristics of PDACs with and without high-grade PanIN.

Method And Results: We reviewed all of a consecutive series of 100 patients with PDACs and divided them into 2 groups: the PDACs with PanIN-2 or PanIN-3 in the background (the PanIN-high group, n = 60) and the PDACs without PanIN-2 or PanIN-3 in the background (the PanIN-low group, n = 40). We evaluated the p53, p16, and SMAD4 expressions in the invasive ductal carcinoma (IDC) components by immunohistochemical staining. KRAS mutation was also analyzed in 80 tumors. The PanIN-low group showed significantly more frequent "high p53 expression" and "loss of SMAD4 expression" than the PanIN-high group (p = 0.048 and p = 0.019, respectively). Loss of p16 expression was not significantly different between the groups. The rate of KRAS wild type was significantly higher in the PanIN-low group than the PanIN-high group (p = 0.024).

Conclusions: Our results demonstrated that the molecular characteristics in the PDACs with high-grade PanIN were different from those in the PDACs without high-grade PanIN. PDACs without high-grade PanIN may develop via a pathway other than the PanIN-carcinoma sequence.
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http://dx.doi.org/10.1159/000455194DOI Listing
January 2018

The impacts of dopamine D2 receptor polymorphism and antipsychotic dosage on dopamine supersensitivity psychosis in schizophrenia.

Schizophr Res 2017 12 9;190:182-183. Epub 2017 Mar 9.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan.

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http://dx.doi.org/10.1016/j.schres.2017.03.014DOI Listing
December 2017

Expression of glucose transporter-1 is correlated with hypoxia-inducible factor 1α and malignant potential in pancreatic neuroendocrine tumors.

Oncol Lett 2016 Nov 5;12(5):3337-3343. Epub 2016 Sep 5.

Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

The present study aimed to investigate the prognostic usefulness of the expression of glucose transporter type 1 (GLUT-1) and GLUT-2, hypoxia-inducible factor 1α (HIF-1α) and insulin-like growth factor II messenger RNA-binding protein 3 (IMP3) in pancreatic neuroendocrine tumors (pNETs). Immunohistochemical staining for GLUT-1, GLUT-2, HIF-1α and IMP3 was performed in 70 pNET specimens. The expression of GLUT-1 and HIF-1α was significantly higher in the World Health Organization grade 2 (G2), neuroendocrine carcinoma cases and mixed-type pNETs compared with the G1 cases. Vessel invasion, a high Ki-67 labeling index and a high mitotic count were significantly more frequent in the GLUT-1- and HIF-1α-positive cases compared with the negative cases. Lymph node metastasis was significantly higher in the GLUT-1-positive cases than in the negative cases. Insulin expression was significantly higher in the IMP3-positive cases than the negative cases. The GLUT-1 expression group experienced a significantly poor disease-free survival rate compared with the negative GLUT-1 expression group. HIF-1α expression was significantly correlated with poor disease-free survival and overall survival rates. A multivariate analysis revealed that lymph node metastasis was an independent risk factor for disease-free survival in all cases. In the G1/G2 group, tumor size and lymph node metastasis were independent risk factors for disease-free survival. Overall, the results suggested that GLUT-1 is a useful prognostic biomarker for pNETs.
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http://dx.doi.org/10.3892/ol.2016.5092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103947PMC
November 2016

Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

Ann Gen Psychiatry 2016 19;15:27. Epub 2016 Oct 19.

Department of Psychiatry, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670 Japan.

Background: This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF.

Methods: We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24.

Results: Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both  < 0.001; and 12.5 vs. 81.8 %,  = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased ( = 8.5,  = 3,  = 0.036) and serum mature BDNF levels were temporarily significantly decreased ( = 3.5,  = 2.4,  = 0.027) in the responders of both groups at week 24.

Conclusion: This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled.
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http://dx.doi.org/10.1186/s12991-016-0115-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070072PMC
October 2016

Increased Serum Levels of Oxytocin in 'Treatment Resistant Depression in Adolescents (TRDIA)' Group.

PLoS One 2016 18;11(8):e0160767. Epub 2016 Aug 18.

Department of Child Psychiatry, Chiba University Hospital, Chiba, Japan.

Objective: 'Treatment-resistant depression' is depression that does not respond to an adequate regimen of evidence-based treatment. Treatment-resistant depression frequently becomes chronic. Children with treatment-resistant depression might also develop bipolar disorder (BD). The objective of this study was to determine whether serum levels of oxytocin (OXT) in treatment-resistant depression in adolescents (TRDIA) differ from non-treatment-resistant depression in adolescents (non-TRDIA) or controls. We also investigated the relationships between serum OXT levels and the clinical symptoms, severity, and familial histories of adolescent depressive patients.

Methods: We measured serum OXT levels: TRDIA (n = 10), non-TRDIA (n = 27), and age- and sex- matched, neurotypical controls (n = 25). Patients were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and the Depression Self-Rating Scale for Children-Japanese Version (DSRS-C-J). The patients were also assessed retrospectively using the following variables: familial history of major depressive disorder and BD (1st degree or 2nd degree), history of disruptive mood dysregulation disorder, recurrent depressive disorder (RDD), history of antidepressant activation.

Results: Serum levels of OXT among the TRDIA and non-TRDIA patients and controls differed significantly. Interestingly, the rates of a family history of BD (1st or 2nd degree), RDD and a history of antidepressant activation in our TRDIA group were significantly higher than those of the non-TRDIA group.

Conclusions: Serum levels of OXT may play a role in the pathophysiology of TRDIA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160767PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990411PMC
August 2017

Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia.

Int J Mol Sci 2015 Dec 17;16(12):30144-63. Epub 2015 Dec 17.

Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan.

Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%-30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.
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http://dx.doi.org/10.3390/ijms161226228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691170PMC
December 2015

Milnacipran treatment and potential biomarkers in depressed patients following an initial SSRI treatment failure: a prospective, open-label, 24-week study.

Neuropsychiatr Dis Treat 2015 10;11:3031-40. Epub 2015 Dec 10.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan ; Department of Psychiatry, Chiba University Hospital, Chiba, Japan.

Background: We assessed the effect of switching patients with major depressive disorder to milnacipran following an initial selective serotonin reuptake inhibitor treatment failure, and explored potential biomarkers in their blood.

Methods: We conducted a prospective, open-label, 24-week trial. Depression was assessed with the 17-item Hamilton Depression Rating Scale. Patients showing a ≥50% reduction in Hamilton Depression Rating Scale scores from baseline to final visit were considered responders. Regarding adverse effects (AEs), moderate-to-severe AEs were specifically identified as effects that required any medical treatment or that induced treatment withdrawals. We also measured blood levels of various molecules including inflammatory cytokines.

Results: Of the 30 participants who enrolled, 17 completed this study. The responder rate was 30% (n=10). Baseline serum levels of interleukin-6 (Z=-2.155; P=0.031) and interleukin-8 (Z=-2.616; P=0.009) were significantly higher when moderate-to-severe AEs were present (n=13 patients with moderate-to-severe AEs). Serum levels of macrophage inflammatory protein-1β showed a significant continuous decrease from the baseline level (Friedman's test: χ (2)=23.9, df=4, P<0.001) only in non-responders.

Conclusion: These results demonstrate that serum levels of interleukin-6, interleukin-8, and macrophage inflammatory protein-1β as potential blood biomarkers could be utilized to identify the responsiveness of patients to serotonin and norepinephrine reuptake inhibitor like milnacipran, or to identify those patients who may experience AEs strong enough to warrant discontinuation of treatment.
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http://dx.doi.org/10.2147/NDT.S95067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677766PMC
December 2015