Publications by authors named "Yoshito Mizoguchi"

64 Publications

No association of both serum pro-brain-derived neurotrophic factor (proBDNF) and BDNF concentrations with depressive state in community-dwelling elderly people.

Psychogeriatrics 2021 Apr 20. Epub 2021 Apr 20.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

Background: Brain-derived neurotrophic factor (BDNF) is involved in emotional and cognitive function. Low-BDNF levels occur in patients with depression, while proBDNF, a precursor of BDNF with the opposite physiological function, increases in major depression. However, it is unclear whether BDNF and proBDNF are associated with depression in the elderly. The present study aimed to investigate whether serum proBDNF and BDNF are associated with depressive state in community-dwelling elderly people.

Methods: This was a cross-sectional study conducted in Kurogawa-cho Imari, Saga Prefecture, Japan, in people aged ≥65 years. Depressive state was assessed using the Geriatric Depression Scale-Short Form (Japanese version) (GDS). Of the 274 patients who undertook the GDS, those with a medical history affecting cognitive function were excluded, as were those with Mini-Mental State Examination score ≥ 24 or a Clinical Dementia Rating < 0.5. Further, we used delayed recall of 'logical memory A' from the Wechsler Memory Scale-Revised (LMII-DR) for memory assessment.

Results: The final sample consisted of 155 individuals (mean age 75.4 ± 6.8 years; 55 men, mean age 74.8 ± 5.9 years; 100 women, mean age 76.3 ± 7.1 years). In the GDS, 139 participants showed a normal score (0-4) and 16 showed depressive tendencies or depression (score: ≥ 5). After examining confounders of the GDS, logistic regression using categorical covariates showed a negative significant difference between depressive state and serum BDNF in the low-BDNF group only, with a positive correlation in the trend test. None of the analyses showed any association between GDS and proBDNF levels.

Conclusion: ProBDNF and BDNF levels seemed not to be associated with depressive state in community-dwelling elderly people.
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http://dx.doi.org/10.1111/psyg.12695DOI Listing
April 2021

The changes in kynurenine metabolites induced by rTMS in treatment-resistant depression: A pilot study.

J Psychiatr Res 2021 Apr 9;138:194-199. Epub 2021 Apr 9.

Department of Psychiatry, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga, 849-8501, Japan.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is considered a valuable and promising technique for improving depressive symptoms in treatment-resistant depression (TRD). However, the exact mechanism by which rTMS ameliorates depressive symptoms remains to be clarified.

Objective: The aim of the present study was to analyzed the changes in metabolites of patients with TRD in the rTMS treatment, especially focusing on the kynurenine (KYN) pathway.

Methods: Thirteen participants with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and the concentration of plasma tryptophan (TRP) metabolites were measured at baseline and at the endpoint of rTMS treatment.

Results: rTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that rTMS treatment significantly increased plasma TRP levels and significantly decreased plasma serotonin levels, while plasma KYN and kynurenic acid level as well as KYN/TRP ratio remained unchanged.

Conclusions: This is the first metabolomic study of patients with TRD undergoing rTMS treatment. To validate the present results, it is necessary to increase the number of cases including controls, use a sample of cerebrospinal fluid, and measure blood concentration over time in the course of rTMS treatment.
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http://dx.doi.org/10.1016/j.jpsychires.2021.04.009DOI Listing
April 2021

The changes in kynurenine metabolites induced by rTMS in treatment-resistant depression: A pilot study.

J Psychiatr Res 2021 Apr 9;138:194-199. Epub 2021 Apr 9.

Department of Psychiatry, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga, 849-8501, Japan.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that is considered a valuable and promising technique for improving depressive symptoms in treatment-resistant depression (TRD). However, the exact mechanism by which rTMS ameliorates depressive symptoms remains to be clarified.

Objective: The aim of the present study was to analyzed the changes in metabolites of patients with TRD in the rTMS treatment, especially focusing on the kynurenine (KYN) pathway.

Methods: Thirteen participants with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and the concentration of plasma tryptophan (TRP) metabolites were measured at baseline and at the endpoint of rTMS treatment.

Results: rTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that rTMS treatment significantly increased plasma TRP levels and significantly decreased plasma serotonin levels, while plasma KYN and kynurenic acid level as well as KYN/TRP ratio remained unchanged.

Conclusions: This is the first metabolomic study of patients with TRD undergoing rTMS treatment. To validate the present results, it is necessary to increase the number of cases including controls, use a sample of cerebrospinal fluid, and measure blood concentration over time in the course of rTMS treatment.
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http://dx.doi.org/10.1016/j.jpsychires.2021.04.009DOI Listing
April 2021

ProBDNF induces sustained elevation of intracellular Ca possibly mediated by TRPM7 channels in rodent microglial cells.

Glia 2021 Mar 19. Epub 2021 Mar 19.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

Microglia are intrinsic immune cells that release factors including pro- and anti-inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca concentration ([Ca ]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF-induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75 ) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca ]i through binding to the p75 , which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro- and anti-inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN-γ and TRPM7 channels could be involved in the proBDNF-induced potentiation of IFN-γ-mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.
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http://dx.doi.org/10.1002/glia.23996DOI Listing
March 2021

Effect of memantine, an anti-Alzheimer's drug, on rodent microglial cells in vitro.

Sci Rep 2021 Mar 17;11(1):6151. Epub 2021 Mar 17.

Department of Psychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

The pathophysiology of Alzheimer's disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-D-aspartate (NMDA) receptors used as an anti-Alzheimer's drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1-42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1-42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1-42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.
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http://dx.doi.org/10.1038/s41598-021-85625-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969939PMC
March 2021

Lower brain-derived neurotrophic factor levels are associated with age-related memory impairment in community-dwelling older adults: the Sefuri study.

Sci Rep 2020 10 5;10(1):16442. Epub 2020 Oct 5.

Department of Psychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

The beneficial effects of brain-derived neurotrophic factor (BDNF)-a member of the neurotrophin family-on cognitive function or dementia are well established in both rodents and human beings. In contrast, little is known about the association of proBDNF-a precursor protein with opposing neuronal effects of BDNF-with cognitive function in non-demented older adults. We analyzed brain magnetic resonance imaging findings of 256 community-dwelling older adults (mean age of 68.4 years). Serum BDNF and proBDNF levels were measured by quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that older age, less physical activity, hippocampal atrophy, and lower BDNF levels were independently associated with memory impairment determined by the Rivermead Behavioral Memory Test. Path analysis based on structural equation modeling indicated that age, sport activity, hippocampal atrophy and BDNF but not proBDNF were individually associated with Rivermead Behavioral Memory Test scores. These findings suggest that impaired BDNF function, in addition to physical inactivity and hippocampal atrophy, is associated with age-related memory impairment. Therefore, BDNF may be a potential target for dementia prevention.
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http://dx.doi.org/10.1038/s41598-020-73576-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536184PMC
October 2020

Oxytocin and elderly MRI-based hippocampus and amygdala volume: a 7-year follow-up study.

Brain Commun 2020 11;2(2):fcaa081. Epub 2020 Jun 11.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga 849-8501, Japan.

Oxytocin is deeply involved in human relations. In recent years, it is becoming clear that oxytocin is also involved in social cognition and social behaviour. Oxytocin receptors are also thought to be present in the hippocampus and amygdala, and the relationship between oxytocin and the structure and function of the hippocampus and amygdala has been reported. However, a few studies have investigated oxytocin and its relationship to hippocampus and amygdala volume in elderly people. The aim of this study is to investigate the association between serum oxytocin levels and hippocampus and amygdala volume in elderly people. The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 596 residents. Serum oxytocin level measurements, brain MRI, Mini-Mental State Examination and Clinical Dementia Rating were performed in Time 1 (2009-11). Follow-up brain MRI, Mini-Mental State Examination and Clinical Dementia Rating were performed in Time 2 (2016-17). The interval between Time 1 and Time 2 was about 7 years. Fifty-eight participants (14 men, mean age 72.36 ± 3.41 years, oxytocin 0.042 ± 0.052 ng/ml; 44 women, mean age 73.07 ± 4.38 years, oxytocin 0.123 ± 0.130 ng/ml) completed this study. We analysed the correlation between serum oxytocin levels (Time 1) and brain volume (Time 1, Time 2 and Times 1-2 difference) using voxel-based morphometry implemented with Statistical Parametric Mapping. Analysis at the cluster level (family-wise error;  < 0.05) showed a positive correlation between serum oxytocin levels (Time 1) and brain volume of the region containing the left hippocampus and amygdala (Time 2). This result suggests that oxytocin in people aged 65 years and older may be associated with aging-related changes in hippocampus and amygdala volume.
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http://dx.doi.org/10.1093/braincomms/fcaa081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472904PMC
June 2020

Changes in interleukin-1 beta induced by rTMS are significantly correlated with partial improvement of cognitive dysfunction in treatment-resistant depression: a pilot study.

Psychiatry Res 2020 07 16;289:112995. Epub 2020 Apr 16.

Department of Psychiatry, Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga 849-8501, Japan. Electronic address:

The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that provides a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). It has recently been demonstrated that TRD is associated with increased inflammatory process. In the present study, we investigated whether a relationship exists between changes in cognitive function and those in inflammatory cytokines before and after rTMS treatment. Eleven patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and serum concentration of inflammatory cytokines (interleukin (IL)-1β, IL-6 and tumor necrosis factor-α) were measured at baseline and at the endpoint of rTMS treatment. rTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that partial changes in cognitive function and changes in IL-1β were significantly correlated. The partial improvement of cognitive dysfunction by rTMS in the present study might be attributable to the reduction of peripheral IL-1β levels. The present results should be replicated for verification in future studies.
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http://dx.doi.org/10.1016/j.psychres.2020.112995DOI Listing
July 2020

Serum Oxytocin Levels and Logical Memory in Older People in Rural Japan.

J Geriatr Psychiatry Neurol 2021 Mar 1;34(2):156-161. Epub 2020 Apr 1.

Department of Psychiatry, 476002Faculty of Medicine, Saga University, Saga, Japan.

Objective: The present study aimed to investigate the relationship between serum oxytocin (OT) and logical memory among older people in rural Japan.

Methods: This was a cross-sectional study using a survey conducted from October 2009 through March 2011. Most of the study was conducted as part of a national prevalence survey of dementia in Japan. The final sample comprised 385 community-dwelling people aged 65 years or older living in rural Japan. The mean age and standard deviation were 75.7 ± 6.76 years (144 men, mean age 75.0 ± 6.48 years; 241 women, mean age 76.2 ± 6.91 years). The participants underwent screening examinations for a prevalence survey of dementia. The screening examinations were the Mini-Mental State Examination, Clinical Dementia Rating, and "logical memory A" from the Wechsler Memory Scale-Revised (WMSR). We used the WMSR Logical Memory II delayed recall score (LM II-DR) to assess logical memory. Levels of serum OT were obtained using the enzyme immunoassay method.

Results: Serum OT levels were significantly higher among women than men. The present study revealed that serum OT levels were positively associated with LM II-DR in older women living in rural Japan in multiple linear regression analyses.

Conclusions: The present results suggested a positive correlation between OT and logical memory in older women living in rural Japan.
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http://dx.doi.org/10.1177/0891988720915526DOI Listing
March 2021

ATP and repetitive electric stimulation increases leukemia inhibitory factor expression in astrocytes: A potential role for astrocytes in the action mechanism of electroconvulsive therapy.

Psychiatry Clin Neurosci 2020 May 5;74(5):311-317. Epub 2020 Mar 5.

Department of Psychiatry, Osaka Medical College, Takatsuki, Japan.

Aim: Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes.

Methods: Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA.

Results: ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it.

Conclusion: P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.
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http://dx.doi.org/10.1111/pcn.12986DOI Listing
May 2020

Improvement Of Frontal Lobe Dysfunction And White Matter Integrity By rTMS In Treatment-Resistant Depression.

Neuropsychiatr Dis Treat 2019 6;15:3079-3087. Epub 2019 Nov 6.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga 849-8501, Japan.

Aim: The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method providing a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). In the present study, we investigated whether a relationship exists between improvements in frontal lobe dysfunction induced by rTMS and improvement of white matter integrity revealed by diffusion tensor imaging (DTI) in TRD patients receiving rTMS treatment.

Methods: A total of 12 patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study (August 2013-January 2019). Frontal lobe function and depressive symptoms were assessed at baseline and at the endpoint of rTMS treatment. Fractional anisotropy (FA), as a measure of white matter integrity obtained from DTI, was investigated using a region-of-interest (ROI) approach.

Results: rTMS treatment significantly improved depressive symptom scores and some subscales of frontal lobe dysfunction. Category scores in the Word Fluency Test and scores on part 3 of the Color Stroop Test were improved independently of the improvement of depressive symptoms. In the ROI analysis, none of the FA increases in any region were correlated with improvement of any frontal lobe function (n = 12).

Conclusion: Although rTMS resulted in partial improvement of frontal lobe dysfunction as well as white matter integrity, we found no correlation between improved frontal lobe dysfunction and improved white matter integrity in TRD patients.
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http://dx.doi.org/10.2147/NDT.S228501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842748PMC
November 2019

Low-Grade Inflammation Is Associated with Apathy Indirectly via Deep White Matter Lesions in Community-Dwelling Older Adults: The Sefuri Study.

Int J Mol Sci 2019 Apr 17;20(8). Epub 2019 Apr 17.

Division of Clinical Research, National Hospital Organization Hizen Psychiatric Center, Saga 842-0192, Japan.

Low-grade inflammation is implicated in the pathogenesis of atherosclerosis, metabolic syndrome, and apathy as a form of vascular depression. We analyzed the brain magnetic resonance imaging findings in 259 community-dwelling older adults (122 men and 137 women, with a mean age of 68.4 years). The serum concentrations of high-sensitivity C-reactive protein (hsCRP) were measured by a quantitative enzyme-linked immunosorbent assay. Logistic regression analysis revealed that the log hsCRP value and the presence of a metabolic syndrome were independently associated with confluent but not punctate deep white matter lesions (DWMLs). Path analysis based on structural equation modeling (SEM) indicated that the direct path from the log hsCRP to the DWMLs was significant (β = 0.119, = 0.039). The direct paths from the metabolic syndrome to the log hsCRP and to the DWMLs were also significant. The direct path from the DWMLs to apathy (β = -0.165, = 0.007) was significant, but the direct path from the log hsCRP to apathy was not significant. Inflammation (i.e., elevated serum hsCRP levels) was associated with DWMLs independent of common vascular risk factors, while DWMLs were associated with apathy. The present analysis with SEM revealed the more realistic scheme that low-grade inflammation was associated with apathy indirectly via DWMLs in community-dwelling older adults.
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http://dx.doi.org/10.3390/ijms20081905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514652PMC
April 2019

Oxytocin levels and sex differences in autism spectrum disorder with severe intellectual disabilities.

Psychiatry Res 2019 03 27;273:67-74. Epub 2018 Dec 27.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

There were few reports of oxytocin (OXT) concentrations of autism spectrum disorder (ASD) patients with severe intellectual disabilities. We measured serum OXT concentrations in 79 hospitalized patients with severe intellectual disabilities (16-60 years old, 50 males and 29 females, 54 ASD patients) and investigated the associations between serum OXT concentration, symptom scores, sex differences, and autism spectrum disorder. There were no significant effects of diagnosis, severity of intellectual disabilities, and total score of the Japanese version of the Aberrant Behavior Checklist (ABC-J), the Childhood Autism Rating Scale-Tokyo Version (CARS-TV), and the Japanese version of the Repetitive Behavior Scale-Revised (RBS-R). However, there were sex differences in the correlations between OXT concentrations and subscale scores in the ASD group. The male ASD group (n = 39) showed negative correlations between RBS-R Self-injurious and Sameness subscale scores and serum OXT concentrations. In the female ASD group(n = 15), CARS-TV Nonverbal communication subscale scores and RBS-R Compulsive subscale scores were seen to positively correlate with serum OXT concentrations. These findings suggest that OXT functions differ in males and females with severe intellectual disabilities and that OXT partly affects autism and related to some of the repetitive behaviors and nonverbal communication, in ASD patients with severe intellectual disabilities.
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http://dx.doi.org/10.1016/j.psychres.2018.12.139DOI Listing
March 2019

The effect of continuous positive airway pressure (CPAP) treatment on serum levels of proBDNF and mature BDNF in patients with obstructive sleep apnea.

Sleep Breath 2019 09 29;23(3):889-892. Epub 2018 Nov 29.

Department of Psychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

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http://dx.doi.org/10.1007/s11325-018-1761-0DOI Listing
September 2019

Cushing's Syndrome and Psychosis: A Case Report and Literature Review.

Prim Care Companion CNS Disord 2018 Sep 13;20(5). Epub 2018 Sep 13.

Department of Psychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan.

Psychiatric complications of Cushing's syndrome include irritability, anxiety, depressed mood, and cognitive impairment. Psychosis is a rare manifestation of Cushing's syndrome; therefore, the literature on the subject is limited and consists mainly of clinical case reports. We report a case of Cushing's syndrome misdiagnosed as schizophrenia-like psychosis for more than 10 years. Transsphenoidal adenomectomy resulted in amelioration of psychiatric symptoms as well as improvement of cognitive ability. Clinicians should consider the presence of psychiatric symptoms predating the diagnosis of Cushing's syndrome, especially when these symptoms are persistent and treatment-resistant, as seen in the present case.
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http://dx.doi.org/10.4088/PCC.18br02279DOI Listing
September 2018

Lamotrigine Rechallenge in Treatment-Resistant Bipolar Disorder.

Prim Care Companion CNS Disord 2018 Mar 29;20(2). Epub 2018 Mar 29.

Saga University, Department of Psychiatry, Nabeshima 5-1-1, Saga-city, Saga 849-8501, Japan.

Background: Although lamotrigine may be useful for treating patients with treatment-resistant bipolar disorder, some lamotrigine-associated adverse effects, including mild to moderate skin rash, may prevent the continuation of treatment.

Methods: We investigated lamotrigine rechallenge for the treatment of bipolar disorder. The present study was based on retrospective chart review of outpatients with bipolar disorder (DSM-5 criteria) who visited the hospital's psychiatric department between July 2011 and August 2017. The review revealed 12 patients with bipolar disorder who underwent lamotrigine rechallenge following lamotrigine discontinuation due to various adverse reactions, including skin rash. None of the patients showed Stevens-Johnson syndrome. All patients suffered from treatment-resistant bipolar disorder that was refractory to treatments other than lamotrigine. For each patient, the severity of the adverse reaction to lamotrigine was weighed against the potential for therapeutic benefit.

Results: In 9 of 12 cases, a positive outcome of lamotrigine rechallenge was observed. In all cases with initial skin rash with very slow titration of lamotrigine, rechallenge was successful with no recurrence of the rash. In the 3 cases for which lamotrigine was unsuccessful, lamotrigine was discontinued owing to movement disorders, ie, oral dyskinesia and action tremor, and liver dysfunction, respectively.

Conclusions: The present results suggest that lamotrigine rechallenge may be a viable option for treatment-resistant bipolar disorder.
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http://dx.doi.org/10.4088/PCC.17m02231DOI Listing
March 2018

Second-Generation Antipsychotic-Induced Hypoglycemia.

Prim Care Companion CNS Disord 2018 01 25;20(1). Epub 2018 Jan 25.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga City, Japan.

Complaints of hypoglycemia resemble the sedative effect of antipsychotics. As such, clinicians may overlook hypoglycemia in patients with psychiatric disorders. Here, a case of hypoglycemia associated with hyperinsulinemia induced by quetiapine in a female patient with bipolar disorder is reported. The case suggests that clinicians should be aware of the potential for hypoglycemia induced by second-generation antipsychotics.
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http://dx.doi.org/10.4088/PCC.17br02186DOI Listing
January 2018

Donepezil suppresses intracellular Ca mobilization through the PI3K pathway in rodent microglia.

J Neuroinflammation 2017 Dec 22;14(1):258. Epub 2017 Dec 22.

Department of Psychiatry, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Background: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca mobilization in microglial cells.

Methods: We examined whether pretreatment with donepezil affects the intracellular Ca mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells.

Results: In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway.

Conclusions: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.
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http://dx.doi.org/10.1186/s12974-017-1033-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741946PMC
December 2017

Effect of Excessive Coffee Consumption on the Clinical Course of a Patient With Bipolar Disorder: A Case Report and Literature Review.

Clin Neuropharmacol 2017 Jul/Aug;40(4):160-162

*Department of Psychiatry, Faculty of Medicine, Saga University; and †Department of Pharmacy, Saga University Hospital, Saga; and ‡Department of Neuropsychiatry, Faculty of Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: The aim of this study was to examine the impact of excessive caffeine consumption on therapeutic outcomes in bipolar disorder.

Methods And Results: We report on a case of a patient with bipolar disorder whose psychiatric symptoms were ameliorated with the elevation of lithium concentrations after the reduction of excessive daily coffee consumption, and we review the relevant literatures.

Conclusions: Excessive coffee consumption may exacerbate the therapeutic course of bipolar disorder through its effects on the mechanisms underlying bipolar disorder itself, as well as by affecting the blood concentration of lithium.
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http://dx.doi.org/10.1097/WNF.0000000000000222DOI Listing
April 2018

TRPC Channels and Brain Inflammation.

Adv Exp Med Biol 2017 ;976:111-121

Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

Nonresolving low-grade inflammation is supposed to underly the basis of chronic disorders including cardiovascular diseases, cancer, diabetes, obesity, and psychiatric disorders such as depression and Alzheimer's diseases. There is increasing evidence suggesting that pathophysiology of psychiatric disorders is related to the inflammatory responses mediated by microglial cells. Elevation of intracellular Ca is important for the activation of microglial cell functions, including proliferation, release of NO, cytokines, and BDNF. It has been shown that alteration of intracellular Ca signaling underlies the pathophysiology of psychiatric disorders, including depression. BDNF induces a sustained intracellular Ca elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. Microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses and may also be involved in the pathophysiology and/or the treatment of psychiatric disorders. We also need to study the effect of proBDNF on microglial cells especially by focusing on the TRPC channels.
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http://dx.doi.org/10.1007/978-94-024-1088-4_10DOI Listing
September 2017

Microglial Intracellular Ca Signaling in Synaptic Development and its Alterations in Neurodevelopmental Disorders.

Front Cell Neurosci 2017 17;11:69. Epub 2017 Mar 17.

Department of Psychiatry, Faculty of Medicine, Saga University Saga, Japan.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by deficits in social interaction, difficulties with language and repetitive/restricted behaviors. Microglia are resident innate immune cells which release many factors including proinflammatory cytokines, nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) when they are activated in response to immunological stimuli. Recent imaging has shown that microglia sculpt and refine the synaptic circuitry by removing excess and unwanted synapses and be involved in the development of neural circuits or synaptic plasticity thereby maintaining the brain homeostasis. BDNF, one of the neurotrophins, has various important roles in cell survival, neurite outgrowth, neuronal differentiation, synaptic plasticity and the maintenance of neural circuits in the CNS. Intracellular Ca signaling is important for microglial functions including ramification, de-ramification, migration, phagocytosis and release of cytokines, NO and BDNF. BDNF induces a sustained intracellular Ca elevation through the upregulation of the surface expression of canonical transient receptor potential 3 (TRPC3) channels in rodent microglia. BDNF might have an anti-inflammatory effect through the inhibition of microglial activation and TRPC3 could play important roles in not only inflammatory processes but also formation of synapse through the modulation of microglial phagocytic activity in the brain. This review article summarizes recent findings on emerging dual, inflammatory and non-inflammatory, roles of microglia in the brain and reinforces the importance of intracellular Ca signaling for microglial functions in both normal neurodevelopment and their potential contributing to neurodevelopmental disorders such as ASDs.
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http://dx.doi.org/10.3389/fncel.2017.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355421PMC
March 2017

Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder.

Front Immunol 2016 9;7:676. Epub 2017 Jan 9.

Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan.

The pathophysiology of bipolar disorder, especially the underlying mechanisms of the bipolarity between manic and depressive states, has yet to be clarified. Microglia, immune cells in the brain, play important roles in the process of brain inflammation, and recent positron emission tomography studies have indicated microglial overactivation in the brain of patients with bipolar disorder. We have recently developed a technique to induced microglia-like (iMG) cells from peripheral blood (monocytes). We introduce a novel translational approach focusing on bipolar disorder using this iMG technique. We hypothesize that immunological conditional changes in microglia may contribute to the shift between manic and depressive states, and thus we herein analyzed gene profiling patterns of iMG cells from three patients with rapid cycling bipolar disorder during both manic and depressive states, respectively. We revealed that the gene profiling patterns are different between manic and depressive states. The profiling pattern of case 1 showed that M1 microglia is dominant in the manic state compared to the depressive state. However, the patterns of cases 2 and 3 were not consistent with the pattern of case 1. CD206, a mannose receptor known as a typical M2 marker, was significantly downregulated in the manic state among all three patients. This is the first report to indicate the importance of shifting microglial M1/M2 characteristics, especially the CD206 gene expression pattern between depressive and manic states. Further translational studies are needed to dig up the microglial roles in the underlying biological mechanisms of bipolar disorder.
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http://dx.doi.org/10.3389/fimmu.2016.00676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220016PMC
January 2017

Aripiprazole inhibits polyI:C-induced microglial activation possibly via TRPM7.

Schizophr Res 2016 12 7;178(1-3):35-43. Epub 2016 Sep 7.

Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.

Viral infections during fetal and adolescent periods, as well as during the course of schizophrenia itself have been linked to the onset and/or relapse of a psychosis. We previously reported that the unique antipsychotic aripiprazole, a partial D2 agonist, inhibits the release of tumor necrosis factor (TNF)-α from interferon-γ-activated rodent microglial cells. Polyinosinic-polycytidylic acid (polyI:C) has recently been used as a standard model of viral infections, and recent in vitro studies have shown that microglia are activated by polyI:C. Aripiprazole has been reported to ameliorate behavioral abnormalities in polyI:C-induced mice. To clarify the anti-inflammatory properties of aripiprazole, we investigated the effects of aripiprazole on polyI:C-induced microglial activation in a cellular model of murine microglial cells and possible surrogate cells for human microglia. PolyI:C treatment of murine microglial cells activated the production of TNF-α and enhanced the p38 mitogen-activated protein kinase (MAPK) pathway, whereas aripiprazole inhibited these responses. In addition, polyI:C treatment of possible surrogate cells for human microglia markedly increased TNF-α mRNA expression in cells from three healthy volunteers. Aripiprazole inhibited this increase in cells from two individuals. PolyI:C consistently increased intracellular Ca concentration ([Ca]) in murine microglial cells by influx of extracellular Ca. We demonstrated that transient receptor potential in melastatin 7 (TRPM7) channels contributed to this polyI:C-induced increase in [Ca]. Taken together, these data suggest that aripiprazole may be therapeutic for schizophrenia by reducing microglial inflammatory reactions, and TRPM7 may be a novel therapeutic target for schizophrenia. Further studies are needed to validate these findings.
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http://dx.doi.org/10.1016/j.schres.2016.08.022DOI Listing
December 2016

Safety of Long-term Use of Lamotrigine for the Treatment of Psychiatric Disorders.

Clin Neuropharmacol 2016 Nov/Dec;39(6):295-298

*Department of Pharmacy, Saga University Hospital; and †Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

Objectives: Lamotrigine (LTG) is a drug commonly used to treat epilepsy and can also be used to manage mood disorders, such as bipolar disorder. One of the most dangerous adverse effects of LTG is skin rash, which can make early cessation necessary. Here, we examine the adverse effects associated with long-term use of LTG for the treatment of mood disorders.

Methods: Data were obtained from the medical records of 101 psychiatric patients who were prescribed long-term treatment with LTG. Patients were retrospectively divided into those who discontinued treatment within 6 months and those who continued for longer, and the groups were compared for adverse effects. We also compared the incidence of adverse effects in high and low doses.

Results: Fifty-four patients continued LTG treatment for 6 months or longer; 47 discontinued within 6 months. A history of allergy was more prevalent among the patients who discontinued treatment early than in those who continued. Of the patients who continued treatment for 6 months or longer, only 2 later discontinued treatment because of adverse effects. Lamotrigine monotherapy showed no difference in the incidence of adverse effects for different doses of LTG (>200 mg = 4.8% vs >100 mg, ≤200 mg = 7.7%; P = 1, vs >50 mg, ≤100 mg = 0%; P = 1 vs ≤50 mg = 0%; P = 1).

Conclusions: Clinicians must be mindful of the adverse effects occurring early during the titration phase. However, long-term use of LTG was very well tolerated, even at high maintenance doses.
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http://dx.doi.org/10.1097/WNF.0000000000000174DOI Listing
January 2017

Aripiprazole-Associated Hypoprolactinemia in the Clinical Setting.

J Clin Psychopharmacol 2016 Aug;36(4):385-7

From the *Department of Pharmacy, Saga University Hospital; and †Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

Background: The increase in prolactin (PRL) levels is a common adverse effect that occurs when using conventional and atypical antipsychotic drugs. Aripiprazole (ARI) is beneficial for antipsychotic-associated hyperprolactinemia but has been reported to decrease PRL secretion. Therefore, we investigated blood levels of PRL in patients who had taken ARI alone or in combination with other antipsychotics.

Methods: Retrospective information was obtained from 25 psychiatric patients who were prescribed ARI, and the blood levels of PRL were measured.

Results: The incidence of hypoprolactinemia in the current study was 44.0% (11/25). Eighteen patients were treated with ARI alone and 7 received ARI in combination with other antipsychotics. The PRL value of patients who took ARI alone was significantly lower than those who were also taking other antipsychotics (5.45 ± 3.93 vs 10.85 ± 5.53, P = 0.02; mean ± SD). There was no significant correlation of the PRL levels and dose of ARI used in the 18 patients who had taken ARI alone.

Limitations: This was a retrospective study, and the data were obtained from a small number of psychiatric patients treated with ARI.

Conclusions: Monitoring of PRL levels in patients treated with ARI may be useful in minimizing hypoprolactinemia, which has the potential to negatively impact patients. In particular, hypoprolactinemia as a consequence of taking ARI should be discussed with patients of childbearing age and those with immune deficiencies.
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http://dx.doi.org/10.1097/JCP.0000000000000527DOI Listing
August 2016

An association between belief in life after death and serum oxytocin in older people in rural Japan.

Int J Geriatr Psychiatry 2017 01 21;32(1):102-109. Epub 2016 Feb 21.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan.

Objective: Previous research suggests that spirituality/religiosity has benefits for both mental and physical health, measured using biological indices such as cortisol and IL-6. However, there have been few studies concerning the association of religious beliefs with oxytocin, a neuropeptide hormone secreted by the pituitary. Levels of peripheral oxytocin are thought to reflect the strength of bonding and stress regulation in social relationships. As such, the oxytocin system may underpin the biological mechanisms by which belief in life after death is associated with good mental and physical health. Here, we examine associations between oxytocin and belief in life after death.

Methods: We recruited 317 community-dwelling people, aged 65 or older, without cognitive or mental deficits, and living in rural Japan. We recorded demographics, belief in life after death, and logical memory using the Wechsler Memory Scale. Levels of serum oxytocin were obtained using an enzyme immunoassay method.

Results: Serum oxytocin levels were higher among women than men and were negatively associated with strength of belief in life after death.

Conclusions: Our findings could be interpreted differently depending on whether the anxiogenic or anxiolytic function of the oxytocin system is considered. Greater endorsement of afterlife beliefs may reduce secure attachment. Alternatively, based on the literature suggesting that basal levels of oxytocin are lower in those with reduced relational distress or anxiety, afterlife beliefs may play a role in these reductions. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/gps.4453DOI Listing
January 2017

Neurocognitive Disorders in Chronic Kidney Disease: A Case Report and Literature Review.

Psychosomatics 2016 Jan-Feb;57(1):107-12. Epub 2015 Jul 29.

Department of Psychiatry, Faculty of Medicine, Saga University, Saga, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.psym.2015.07.007DOI Listing
January 2017

Abnormal behaviours during pramipexole treatment for Cotard's syndrome: a case report.

Psychogeriatrics 2016 Jul 29;16(4):283-286. Epub 2015 Sep 29.

Department of Psychiatry, Saga University Hospital, Saga, Japan.

Cotard's syndrome is a relatively rare condition that involves a delusion of negation in which an individual believes he or she has lost his or her soul, is dead, or is without functional body systems. This syndrome is observed in various neuropsychiatric disorders but most commonly in mood disorders. Pramipexole has often been used in the adjunctive treatment of both bipolar and unipolar depression, and it is known to cause rare but serious adverse effects such as compulsive behaviours in the treatment of Parkinson's disease. Here we report a case of Cotard's syndrome in treatment-resistant major depression associated with abnormal behaviours that might be caused by pramipexole. In the present case, the patient's abnormal behaviours gradually disappeared about 2 months after the discontinuation of pramipexole. The hypoperfusion in the bilateral parieto-occipital lobe found on single-photon emission computed tomography suggests the presence of Lewy body disease pathology. Nonetheless, the patient's abnormal behaviours disappeared after the discontinuation of pramipexole, indicating that they are mainly attributable to pramipexole treatment. However, the possible existence of Lewy body pathology could facilitate the emergence of abnormal behaviours after treatment with pramipexole. The patient's abnormal behaviours, such as eating other patients' food and taking her medicine before the scheduled time, might differ from typical compulsive behaviours induced by pramipexole (such as pathological gambling and hypersexuality), but they could be regarded as disinhibition. Therefore, we should follow up on the clinical course of this case carefully through neuroimaging investigation and neurocognitive assessment.
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http://dx.doi.org/10.1111/psyg.12148DOI Listing
July 2016

A patient with Alzheimer's disease complicated by elderly-onset Cushing's syndrome who had undergone surgical treatment for adrenocorticotropic hormone-independent macronodular adrenal hyperplasia.

Psychogeriatrics 2016 Jul 15;16(4):274-276. Epub 2015 Sep 15.

Department of Psychiatry, Saga University Hospital, Saga, Japan.

Cushing's syndrome (CS) is a rare disorder, especially in older people. Loss of brain volume and neurocognitive impairment of varying degrees has been demonstrated in patients with CS. However, there is a large difference between the median age of presentation of CS and that of Alzheimer's disease. We herein report a case of a patient with Alzheimer's disease complicated by elderly-onset CS who had undergone surgical treatment for adrenal hyperplasia. Surgical correction of hypercortisolism seems to have slowed the progression of brain volume loss and cognitive dysfunction and improved psychiatric symptoms such as visual hallucination, restlessness, and psychomotor excitement. These improvements have remarkably reduced the burden on the patient's caregivers. The present case suggests that subclinical CS may be present, particularly in rapidly progressive dementia, and that surgical treatment of CS for neuropsychiatric symptoms is useful.
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http://dx.doi.org/10.1111/psyg.12146DOI Listing
July 2016

[Immune system and psychiatric disorders: involvement of BDNF and intracellular Ca2+ signaling].

Seishin Shinkeigaku Zasshi 2014 ;116(10):832-41

Nonresolving low-grade inflammation is supposed to underly the basis of chronic disorders including cancer, type 2 diabetes, cardiovascular diseases, obesity and psychiatric disorders such as depression. There is increasing evidence suggesting that pathophysiology of psychiatric disorders is related to the inflammatory responses mediated by microglial cells. Elevation of intracellular Ca2+ is important in activation of microglial cell functions, including proliferation, release of NO, cytokines and BDNF. It has been shown that alteration of intracellular Ca2+ signaling underlies the pathophysiology of psychiatric disorders, including schizophrenia, depression and bipolar disorders. Microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of psychiatric disorders.
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March 2015