Hiroshi Kunugi

National Center of Neurology and Psychiatry, Кодаиры, Tōkyō, Japan

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Publications (343)1569.93 Total impact

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    ABSTRACT: Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Neuroscience Letters 05/2015; 599. DOI:10.1016/j.neulet.2015.05.019 · 2.06 Impact Factor
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    ABSTRACT: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. Previous studies suggested that l-theanine affects the glutamatergic neurotransmission and ameliorates symptoms in patients with schizophrenia. The aims of the present study were twofold: to examine the possible effects of l-theanine on symptoms in chronic schizophrenia patients and to evaluate the changes in chemical mediators, including glutamate + glutamine (Glx), in the brain by using 1H magnetic resonance spectroscopy (MRS). The subjects were 17 patients with schizophrenia and 22 age- and sex-matched healthy subjects. l-Theanine (250 mg/day) was added to the patients' ongoing antipsychotic treatment for 8 weeks. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), Pittsburgh Sleep Quality Index scores and MRS results. There were significant improvements in the PANSS positive scale and sleep quality after the l-theanine treatment. As for MRS, we found no significant differences in Glx levels before and after the 8 week l-theanine treatment. However, significant correlations were observed between baseline density of Glx and change in Glx density by l-theanine. Our results suggest that l-theanine is effective in ameliorating positive symptoms and sleep quality in schizophrenia. The MRS findings suggest that l-theanine stabilises the glutamatergic concentration in the brain, which is a possible mechanism underlying the therapeutic effect.
    Acta Neuropsychiatrica 04/2015; DOI:10.1017/neu.2015.22 · 0.64 Impact Factor
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    ABSTRACT: Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipo-lar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub-threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed.
    PLoS ONE 04/2015; DOI:10.1371/journal.pone.0122711 · 3.53 Impact Factor
  • Hiroshi Kunugi, Hiroaki Hori, Shintaro Ogawa
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    ABSTRACT: The pathophysiology of major depressive disorder (MDD) remains elusive, and there is no established biochemical marker used in the daily clinical setting. This situation may result in part from the heterogeneity of MDD which might include heterogeneous subgroups with different biological mechanisms. In this review, we discuss three promising biological systems/markers to potentially subtype MDD, that is, dopamine system, hypothalamic-pituitary-adrenal (HPA) axis, and chronic inflammatory markers. Several lines of evidence suggest that a portion of MDD is a dopamine agonist-responsive subtype. Focusing on the HPA axis, depressive spectrum disorders show hypercortisolism to hypocortisolism which could be detected by hormonal challenge tests such as the dexamethasone/corticotropin releasing hormone test. Finally, accumulating evidence suggests that at least a portion of MDD patients show characteristics similar to those of chronic inflammatory diseases including neuroinflammatory markers and reduced tryptophan due to the increased activation of the tryptophan-kynureline pathway. Future studies should examine the inter-relationships between these systems/markers to subtype and integrate the pathophysiology of MDD. This article is protected by copyright. All rights reserved.
    Psychiatry and Clinical Neurosciences 03/2015; DOI:10.1111/pcn.12299 · 1.62 Impact Factor
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    ABSTRACT: Intrauterine growth restriction (IUGR) is a risk factor for memory impairment and emotional disturbance during growth and adulthood. However, this risk might be modulated by environmental factors during development. Here we examined whether exposing adolescent male and female rats with thromboxane A2-induced IUGR to social defeat stress (SDS) affected their working memory and anxiety-like behavior in adulthood. We also used BrdU staining to investigate hippocampal cellular proliferation and BrdU and NeuN double staining to investigate neural differentiation in female IUGR rats. In the absence of adolescent stress, IUGR female rats, but not male rats, scored significantly lower in the T-maze test of working memory and exhibited higher anxiety-like behavior in the elevated-plus maze test compared with controls. Adolescent exposure to SDS abolished these behavioral impairments in IUGR females. In the absence of adolescent stress, hippocampal cellular proliferation was significantly higher in IUGR females than in non-IUGR female controls and was not influenced by adolescent exposure to SDS. Hippocampal neural differentiation was equivalent in non-stressed control and IUGR females. Neural differentiation was significantly increased by adolescent exposure to SDS in controls but not in IUGR females. There was no significant difference in the serum corticosterone concentrations between non-stressed control and IUGR females; however, adolescent exposure to SDS significantly increased serum corticosterone concentration in control females but not in IUGR females. These results demonstrate that adolescent exposure to SDS improves behavioral impairment independent of hippocampal neurogenesis in adult rats with IUGR. Copyright © 2015. Published by Elsevier Inc.
    Hormones and Behavior 02/2015; 70. DOI:10.1016/j.yhbeh.2015.01.010 · 4.51 Impact Factor
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    ABSTRACT: Previous studies demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents have been suggested as a useful model of schizophrenia. This study was aimed to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [(18)F]fallypride as a radioligand to estimate the release in a rat model of schizophrenia. Six rats were scanned by positron emission tomography (PET) twice before and after methylphenidate challenge to evaluate dopamine release. After the scans, these rats were sensitized by using repeated methamphetamine (MAP) administration. Then, they were re-scanned twice again before and after methylphenidate challenge to evaluate whether MAP-sensitized rats show greater sensitivity to methylphenidate. We revealed a main effect of MAP-pretreatment and that of metylphenidate challenge. We found that % change of distribution volume ratio after repeated administration of MAP was greater than that before sensitization. These results suggest that methylphenidate-induced striatal dopamine release increased after sensitization to MAP. PET scan using [(18)F]fallypride at methylphenidate-challenge may provide a biological marker for schizophrenia and be useful to diagnose schizophrenia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research Neuroimaging 02/2015; 232(1). DOI:10.1016/j.pscychresns.2015.01.023 · 2.83 Impact Factor
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    ABSTRACT: Amino acids play key roles in the function of the central nervous system, and their alterations are implicated in psychiatric disorders. In the search for a biomarker for major depressive disorder (MDD), we used high-performance liquid chromatography to measure amino acids and related molecules in the cerebrospinal fluid (CSF) of 52 patients with MDD (42 depressed and 10 remitted; DSM-IV) and 54 matched controls. Significant differences were found in four amino acid concentrations between the depressed patients and controls. After Bonferroni correction, only ethanolamine (EA) levels remained significantly reduced in depressed patients (nominal P = 0.0000011). A substantial proportion of the depressed patients (40.5%) showed abnormally low CSF EA levels (<12.1 μM) (P = 0.000033; OR = 11.6, 95% CI: 3.1-43.2). When patients with low EA and those with high EA levels were compared, the former had higher scores for overall depression severity (P = 0.0033) and 'Somatic Anxiety' symptoms (P = 0.00026). In unmedicated subjects, CSF EA levels showed a significant positive correlation with levels of homovanillic acid (P = 0.0030) and 5-hydroxyindoleacetic acid (P = 0.019). To our knowledge, this is the first study showing that patients with MDD have significantly lower CSF EA concentrations compared with control subjects. CSF EA could be a state-dependent biomarker for a subtype of MDD.
    Scientific Reports 01/2015; 5:7796. DOI:10.1038/srep07796 · 5.58 Impact Factor
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    ABSTRACT: Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.0011). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities.
    Scientific Reports 01/2015; 5:11412. DOI:10.1038/srep11412 · 5.58 Impact Factor
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    ABSTRACT: Evidence suggests that neuronal microRNAs (miRs) contribute to synaptic plasticity, although a role of glial miRs have been unknown. Growth factors including brain-derived neurotrophic factor (BDNF) regulate neuronal functions via upregulation of miRs, while possible influences on expression/function of glial miRs have not been fully understood. Here, we report that basic fibroblast growth factor (bFGF) increased miR-134 expression in astrocyte. The miR-134 was upregulated through stimulating extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling, because inhibitors for each signaling blocked the miR-134 induction by bFGF. We also found upregulation of glial fibrillary acidic protein (astrocyte marker) and decreased extracellular concentration of glutamate after miR-134 overexpression and bFGF application, suggesting that astroglial cell maturation is enhanced by bFGF through induction of miR-134. Copyright © 2014. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 12/2014; 456(1). DOI:10.1016/j.bbrc.2014.11.108 · 2.28 Impact Factor
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    ABSTRACT: Negative symptoms (e.g., decreased spontaneity, social withdrawal, blunt affect) and disturbances of cognitive function (e.g., several types of memory, attention, processing speed, executive function, fluency) provide a major determinant of long-term outcome in patients with schizophrenia. Specifically, motivation deficits, a type of negative symptoms, have been attracting interest as (1) a moderator of cognitive performance in schizophrenia and related disorders, and (2) a modulating factor of cognitive enhancers/remediation. These considerations suggest the need to clarify neurobiological substrates regulating motivation. Genetic studies indicate a role for the monoamine systems in motivation and key cognitive domains. For example, polymorphism of genes encoding catecholamine-O-methyltransferase, an enzyme catabolizing dopamine (DA), affects performance on tests of working memory and executive function in a phenotype (schizophrenia vs. healthy controls)-dependent fashion. On the other hand, motivation to maximize rewards has been shown to be influenced by other genes encoding DA-related substrates, such as DARPP-32 and DA-D2 receptors. Serotonin (5-HT) receptors may also play a significant role in cognitive and motivational disabilities in psychoses and mood disorders. For example, mutant mice over-expressing D2 receptors in the striatum, an animal model of schizophrenia, exhibit both decreased willingness to work for reward and up-regulation of 5-HT2C receptors. Taken together, genetic predisposition related to 5-HT receptors may mediate the diversity of incentive motivation that is impaired in patients receiving biological and/or psychosocial treatments. Thus, research into genetic and neurobiological measures of motivation, in association with 5-HT receptors, is likely to facilitate intervention into patients seeking better social consequences.
    Frontiers in Neuroscience 12/2014; 8:395. DOI:10.3389/fnins.2014.00395 · 3.70 Impact Factor
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer's disease, Huntington's disease, depression and schizophrenia.
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    ABSTRACT: Background Recently great attention has been paid to the still unmet clinical needs of most adults with autism spectrum disorder (ASD) who live in the community, an increasing number of whom visit psychiatric clinics to seek accurate diagnosis and treatment of concurrent psychiatric symptoms. However, different from the case of children diagnosed with ASD in childhood, it is difficult in adults to identify the ASD symptoms underlying psychopathology and to differentiate ASD from other psychiatric disorders in general psychiatric practice. This study aimed to verify the utility of the Social Responsiveness Scale-Adult version (SRS-A), a quantitative measure for identifying ASD symptoms, in non-clinical and clinical adult populations in Japan. Methods The total sample aged 19 to 59 years consisted of a non-clinical population (n =592) and clinical population with and without ASD (n =142). We examined score distributions of the Japanese version of the scale, and the effects of gender, age, and rater on the distribution. We analyzed factor structure and internal consistency in the non-clinical normative sample, and analyzed convergent, divergent, and discriminative validities in the clinical sample. We applied receiver operator characteristic (ROC) analysis to determine optimal cutoff scores discriminating the ASD clinical population from the non-ASD clinical population. Results The score distributed continuously, which replicated findings in children. For non-clinical adults, except in men aged 19 to 24 years, we found no or few gender, age, or rater effects. Both single- and two-factor models were supported for adults. Total SRS-A scores demonstrated high internal consistency and capably discriminated adults with ASD from those with non-ASD psychiatric disorders such as major depressive disorder, schizophrenia, and bipolar disorder with an overlap across diagnoses. Moderate to high correlations of the SRS-A with other-rated ASD measures indicated sufficient convergent validity. Based on the ROC analysis, we recommend cutoff points by gender for use in clinical settings. Conclusion This study provides additional supportive evidence that the Japanese version SRS-A can reliably and validly measure ASD symptoms in non-clinical and clinical adult populations, and thus can serve as a useful tool for ASD research as well as for secondary screening in Japanese adults.
    BMC Psychiatry 11/2014; DOI:10.1186/s12888-014-0302-z · 2.24 Impact Factor
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    ABSTRACT: FK506 binding protein 5 (FKBP5) is induced by stress and regulates glucocorticoid receptor sensitivity. The T allele of the single nucleotide polymorphism (SNP) FKBP5 rs1360780 (C/T) is associated with an increased risk of post-traumatic stress disorder (PTSD) and reduced hippocampal volume in traumatized or depressed subjects. To examine whether this SNP affects brain structures that regulate stress response, we obtained magnetic resonance imaging data of the brain in 162 healthy subjects using a 1.5 Tesla system. Gray matter volumes and diffusion tensor imaging data were compared between individuals with and without the T allele, using optimized voxel-based morphometry. We found that the dorsal anterior cingulate cortex (dACC) volume was smaller in T carriers than in non-T carriers (P < 0.001). T carriers also showed significantly higher mean diffusivity values in the dACC and posterior cingulate cortex (PCC) compared with non-T carriers (P < 0.001). Our results suggest that carrying the T allele of FKBP5 rs1360780 is associated with smaller gray matter volumes in the dACC and altered white matter integrity in the dACC and PCC in the non-clinical population, which might constitute the structural basis of stress-related psychiatric disorders including PTSD.
    Journal of Psychiatric Research 11/2014; 58. DOI:10.1016/j.jpsychires.2014.07.009 · 4.09 Impact Factor
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    ABSTRACT: AimThe Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) recognizes some subtypes of major depressive disorder (MDD). It is known that the effectiveness of antidepressants differs among the MDD subtypes, and thus the differentiation of the subtypes is important. However, little is known as to structural brain changes in MDD with atypical features (aMDD) in comparison with MDD with melancholic features (mMDD), which prompted us to examine possible differences in white matter integrity assessed with diffusion tensor imaging (DTI) between these two subtypes.Methods Subjects were 21 patients with mMDD, 24 with aMDD, and 37 age- and sex-matched healthy volunteers whose DTI data were obtained by 1.5 tesla magnetic resonance imaging. We compared fractional anisotropy (FA) and mean diffusivity (MD) value derived from DTI data on a voxel-by-voxel basis among the 2 diagnostic groups and healthy subjects.ResultsThere were significant decreases of FA and increases of MD in patients with MDDs compared with healthy subjects in the corpus callosum, inferior fronto-occipital fasciculus, and left superior longitudinal fasciculus. However, we detected no significant difference in any brain region between mMDD and aMDD.Conclusion Our results suggest that patients with MDD had reduced white matter integrity in some regions; however, there was no major difference between aMDD and mMDD.
    Psychiatry and Clinical Neurosciences 11/2014; 69(6). DOI:10.1111/pcn.12255 · 1.62 Impact Factor
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    ABSTRACT: The common single nucleotide polymorphism (SNP) rs1360780 (C/T) of the FK506 Binding Protein 5 (FKBP5) gene has been reported to be associated with an altered response of the hypothalamic-pituitary-adrenal (HPA) axis and the development of stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). In the present study, we examined whether this SNP is associated with cognitive function in a non-clinical population. The full versions of the Wechsler Memory Scale-Revised and Wechsler Adult Intelligence Scale-Revised were administered to 742 and 627 Japanese individuals, respectively, followed by genotyping of rs1360780 by the TaqMan 5'-exonuclease allelic discrimination assay. For both cognitive tests, we found significantly poorer attention/concentration (working memory) in aged (>50 years old) individuals carrying the T allele compared with their counterparts. This finding accords with an altered HPA axis and vulnerability to stress-related psychiatric disorders.
    Scientific Reports 10/2014; 4:6696. DOI:10.1038/srep06696 · 5.58 Impact Factor
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    ABSTRACT: Background: Nuclear distribution E homolog 1 (NDE1), located within chromosome 16p13.11, plays an essential role in microtubule organization, mitosis, and neuronal migration and has been suggested by several studies of rare copy number variants to be a promising schizophrenia (SCZ) candidate gene. Recently, increasing attention has been paid to rare single-nucleotide variants (SNVs) discovered by deep sequencing of candidate genes, because such SNVs may have large effect sizes and their functional analysis may clarify etiopathology. Methods and Results: We conducted mutation screening of NDE1 coding exons using 433 SCZ and 145 pervasive developmental disorders samples in order to identify rare single nucleotide variants with a minor allele frequency ≤5%. We then performed genetic association analysis using a large number of unrelated individuals (3554 SCZ, 1041 bipolar disorder [BD], and 4746 controls). Among the discovered novel rare variants, we detected significant associations between SCZ and S214F (P = .039), and between BD and R234C (P = .032). Furthermore, functional assays showed that S214F affected axonal outgrowth and the interaction between NDE1 and YWHAE (14-3-3 epsilon; a neurodevelopmental regulator). Conclusions: This study strengthens the evidence for association between rare variants within NDE1 and SCZ, and may shed light into the molecular mechanisms underlying this severe psychiatric disorder.
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    ABSTRACT: Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF), glucocorticoid levels (one of the steroid hormones), and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the cross-talk among cytokines, BDNF, and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids) on BDNF-mediated brain functions.
    Frontiers in Psychiatry 09/2014; 5:136. DOI:10.3389/fpsyt.2014.00136
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    ABSTRACT: Patients with schizophrenia are at increased risk for suicide. Various risk factors for suicide have been reported in schizophrenia; however, few studies have examined the association between personality traits and suicidal behavior. We administered the Schizotypal Personality Questionnaire (SPQ) to 87 Japanese patients with schizophrenia (49 males; mean age 38.1±10.6 years) with and without a history of suicide attempts (SA and nSA groups, respectively), and 322 controls (158 males; mean age 40.8±13.9 years). As expected, an analysis of covariance (ANCOVA) controlling for age and sex showed that all SPQ indices (total SPQ score and all three factors, i.e., cognitive-perceptual, interpersonal, and disorganized) were significantly higher in patients with schizophrenia (SA+nSA groups), than controls (p<0.001 for all comparisons). Furthermore, there were significant differences in the total score and the interpersonal and disorganized factors between the SA and nSA groups (nSA<SA, p<0.01 for all comparisons). Receiver operating characteristic analysis showed that a total SPQ score of 33.5 was the optimal cut-off value to discriminate the SA group from the nSA group (χ2[1] = 10.6, p = 0.002, odds ratio: 4.7, 95% confidence interval: 1.8-12.1, sensitivity: 0.70, specificity: 0.67). These results suggest that high schizotypy is associated with lifetime suicide attempts, and that the total SPQ score might be useful to assess the risk of suicide attempt in patients with schizophrenia.
    PLoS ONE 09/2014; 9(9):e107739. DOI:10.1371/journal.pone.0107739 · 3.53 Impact Factor
  • Hyung Shin Yoon, Naoki Adachi, Hiroshi Kunugi
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    ABSTRACT: Cocaine- and amphetamine-regulated transcript (CART) peptide is abundantly expressed in the nucleus accumbens (NAcc) and is involved in stress, anxiety and reward responses. To examine the role of CART peptide in anxiety-related behavior, naïve rats were bilaterally injected with CART 55-102 peptide (0.5, 1.0 or 2.5 μg/0.5 μl/side) or vehicle into the NAcc. Following this, their anxiety-related behavior was assessed using the elevated plus maze and the open field tests with a one-week interval between the tests. There was no difference in the time spent in open arms, or number of entries into open arms on the elevated plus maze in the CART-treated animals at any dose, when compared with the vehicle-treated group. However, there was a significant increase in the time spent in the center of the open field with administration of the low dose of CART peptide (0.5 μg/0.5 μl/side), although this effect disappeared at the high dose (2.5 μg/0.5 μl/side). None of the doses of CART peptide altered total locomotion in these tests. To further determine the possible anxiety-modulating effect of CART peptide at low dosages, the light and dark test was performed. Additional groups of rats given doses of 0.01 μg/0.5 μl/side or 0.5 μg/0.5 μl/side of CART peptide showed increased exploration time in the light side. These results suggest that accumbal-CART peptide reduces anxiety-like behavior in a dose-dependent manner.
    Neuropeptides 09/2014; DOI:10.1016/j.npep.2014.09.002 · 2.55 Impact Factor

Publication Stats

7k Citations
1,569.93 Total Impact Points


  • 1970–2015
    • National Center of Neurology and Psychiatry
      • Department of Mental Disorder Research
      Кодаиры, Tōkyō, Japan
  • 2010–2014
    • Japan Science and Technology Agency (JST)
      Edo, Tōkyō, Japan
  • 2011
    • St. Marianna University School of Medicine
      • Department of Physiology
      Kawasaki Si, Kanagawa, Japan
  • 2006
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
    • Shukutoku University
      Koromo, Aichi, Japan
  • 2004
    • Kyorin University
      Edo, Tōkyō, Japan
  • 1994–2004
    • Teikyo University
      • Department of Medicine
      Edo, Tōkyō, Japan
  • 1993–2004
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
  • 2003
    • RIKEN
      • Laboratory for Molecular Dynamics of Mental Disorders
      Wako, Saitama-ken, Japan
  • 1996–2000
    • Juntendo University
      • Department of Psychiatry
      Edo, Tōkyō, Japan
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • New South Wales Institute of Psychiatry
      Sydney, New South Wales, Australia
    • Zhejiang University
      • Department of Physics
      Hangzhou, Zhejiang Sheng, China
  • 1998
    • Tokyo Metropolitan Geriatric Medical Center
      Edo, Tōkyō, Japan