Publications by authors named "Tetsuya Ando"

26 Publications

  • Page 1 of 1

Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive-behavioural therapy for eating disorders.

BMJ Open 2021 01 25;11(1):e042685. Epub 2021 Jan 25.

Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan

Introduction: Anorexia nervosa is a refractory psychiatric disorder with a mortality rate of 5.9% and standardised mortality ratio of 5.35, which is much higher than other psychiatric disorders. The standardised mortality ratio of bulimia nervosa is 1.49; however, it is characterised by suicidality resulting in a shorter time to death. While there is no current validated drug treatment for eating disorders in Japan, cognitive-behavioural therapy (CBT) is a well-established and commonly used treatment. CBT is also recommended in the Japanese Guidelines for the Treatment of Eating Disorders (2012) and has been covered by insurance since 2018. However, the neural mechanisms responsible for the effect of CBT have not been elucidated, and the use of biomarkers such as neuroimaging data would be beneficial.

Methods And Analysis: The Eating Disorder Neuroimaging Initiative is a multisite prospective cohort study. We will longitudinally collect data from 72 patients with eating disorders (anorexia nervosa and bulimia nervosa) and 70 controls. Data will be collected at baseline, after 21-41 sessions of CBT and 12 months later. We will assess longitudinal changes in neural circuit function, clinical data, gene expression and psychological measures by therapeutic intervention and analyse the relationship among them using machine learning methods.

Ethics And Dissemination: The study was approved by The Ethical Committee of the National Center of Neurology and Psychiatry (A2019-072). We will obtain written informed consent from all patients who participate in the study after they had been fully informed about the study protocol. All imaging, demographic and clinical data are shared between the participating sites and will be made publicly available in 2024.

Trial Registration Number: UMIN000039841.
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http://dx.doi.org/10.1136/bmjopen-2020-042685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839914PMC
January 2021

Urocortin 1: A putative excitatory neurotransmitter in the enteric nervous system.

Neurogastroenterol Motil 2020 10 20;32(10):e13842. Epub 2020 Mar 20.

Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: Urocortin 1 (Ucn1), a stress-related peptide, is a member of the corticotropin-releasing factor (CRF) family and acts as a CRF1 receptor agonist. Ucn1 and CRF1 receptor immunoreactivity are present in the enteric nervous system (ENS), and Ucn1 elicits contraction of colonic muscle strips. Considering these findings, we have hypothesized that Ucn1 acts as an excitatory neurotransmitter in the ENS. The present study was conducted to determine whether exogenously applied Ucn1 causes contractions, whether it participates in neurally mediated contraction, and whether it is released from the ENS of the rat colon.

Methods: Isometric tension of the rat colonic muscle strips (middle to distal colon) in a longitudinal direction was measured. The effects of Ucn1 on phasic contractions were examined in the absence and presence of antalarmin (CRF1 receptor antagonist), tetrodotoxin (TTX), and atropine. The effects of antalarmin on electrical field stimulation (EFS)-induced contractions were examined in the absence and presence of atropine. Ucn1 peptide in the bath solution was measured after EFS using an EIA kit.

Key Results: Ucn1 caused a significant and dose-dependent increase in phasic contractions. These effects were completely inhibited by antalarmin, TTX, and atropine. EFS-induced contractions were inhibited by antalarmin. Atropine markedly reduced EFS-induced contractions, and antalarmin did not decrease these contractions further. EFS elicited a significant increase in the concentration of Ucn1 in the bath solution, and this increase was completely inhibited by TTX.

Conclusions And Inferences: These results suggest that Ucn1 acts as an excitatory neurotransmitter in the ENS enhancing the cholinergic neurotransmission.
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http://dx.doi.org/10.1111/nmo.13842DOI Listing
October 2020

Effectiveness of enhanced cognitive behavior therapy for bulimia nervosa in Japan: a randomized controlled trial protocol.

Biopsychosoc Med 2020 24;14. Epub 2020 Feb 24.

1Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8553 Japan.

Background: The effectiveness of psychotherapeutic interventions for eating disorders (EDs) is widely studied in Europe, North America, and Australia/New Zealand. However, few controlled studies and no randomized controlled trials (RCTs) have been conducted in Japan despite the relatively high prevalence of EDs in the Japanese population. The aim of this study is to evaluate the effect of enhanced cognitive behavior therapy (CBT-E), an evidence-supported ED-focused form of cognitive behavior therapy (CBT), for the treatment of bulimia nervosa (BN) in Japan.

Methods/design: This multicenter RCT will compare CBT-E with treatment as usual (TAU), which is widely used in Japan. A group of 140 adult outpatients with a Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) diagnosis of BN, ≥18 years of age, a body mass index (BMI) > 17.5 and < 40 kg/m will be randomly assigned to CBT-E or TAU. Participants will be stratified by intervention site and BN severity. CBT-E participants will receive 20 sessions of focused form CBT-E for 20 weeks. Those in the TAU group will receive routine treatment provided by specialists. Assessment will be performed in a blinded manner prior to the start of treatment, after 6 weeks of treatment, at the end of treatment (20 weeks), and at follow-up at 40 and 80 weeks after the start of treatment. The primary outcome is the remission of BN, defined by the absence, in the previous 4 weeks, of symptoms required to meet the DSM-5 criteria for a diagnosis of BN. Secondary outcomes include the levels of ED psychopathology and impairment due to the ED, anxiety, depression, family function, and satisfaction with treatment.

Discussion: This will be the first RCT conducted in Japan to compare CBT-E and TAU for the treatment of BN. If CBT-E is found to be more effective than TAU, then the evidence would support its wider use for patients with BN in Japan. Because it is possible to train therapists who do not possess extensive specialist experience, wider use is also likely to be practically feasible. In addition, demonstrating the effectiveness of CBT-E in Japan would demonstrate that it could be successfully extended to additional world cultures and regions.

Trial Registration: UMIN, UMIN000031625. Registered 7 Mar 2018.
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http://dx.doi.org/10.1186/s13030-020-0174-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041176PMC
February 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Nat Genet 2019 08 15;51(8):1207-1214. Epub 2019 Jul 15.

Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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http://dx.doi.org/10.1038/s41588-019-0439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779477PMC
August 2019

Cognitive behavioral therapy with interoceptive exposure and complementary video materials for irritable bowel syndrome (IBS): protocol for a multicenter randomized controlled trial in Japan.

Biopsychosoc Med 2019 6;13:14. Epub 2019 Jun 6.

1Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry (NCNP), Kodaira, 187-8553 Japan.

Background: There is growing evidence of the treatment efficacy of cognitive behavioral therapy (CBT) for irritable bowel syndrome (IBS). CBT is recommended by several practice guidelines for patients with IBS if lifestyle advice or pharmacotherapy has been ineffective. Manual-based CBT using interoceptive exposure (IE), which focuses on the anxiety response to abdominal symptoms, has been reported to be more effective than other types of CBT. One flaw of CBT use in general practice is that it is time and effort consuming for therapists. Therefore, we developed a set of complementary video materials that include psycho-education and homework instructions for CBT patients, reducing time spent in face-to-face sessions while maintaining treatment effects. The purpose of this study is to examine the effects of CBT-IE with complementary video materials (CBT-IE-w/vid) in a multicenter randomized controlled trial (RCT).

Methods: This study will be a multicenter, parallel-design RCT. Participants diagnosed with IBS according to the Rome IV diagnostic criteria will be randomized to either the treatment as usual (TAU) group or the CBT-IE-w/vid + TAU group. CBT-IE-w/vid consists of 10 sessions (approximately 30 min face-to-face therapy + viewing a video prior to each session). Patients in the CBT-IE-w/vid group will be instructed to pre- view 3- to 13-min videos at home prior to each face-to-face therapy visit at a hospital. The primary outcome is the severity of IBS symptoms. All participants will be assessed at baseline, mid-treatment, post-treatment, and follow-up (3 months after post assessment). The sample will include 60 participants in each group.

Discussion: To our knowledge, this study will be the first RCT of manual-based CBT for IBS in Japan. By using psycho-educational video materials, the time and cost of therapy will be reduced. Manual based CBTs for IBS have not been widely adopted in Japan to date. If our CBT-IE-w/vid program is confirmed to be more effective than TAU, it will facilitate dissemination of cost-effective manual-based CBT in clinical settings.

Trial Registration: The trial was registered to the University Hospital Medical Information Network Clinical Trial Registry: UMIN, No. UMIN000030620 (Date of registration: December 28, 2017).
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http://dx.doi.org/10.1186/s13030-019-0155-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551860PMC
June 2019

Negatively Skewed Locomotor Activity Is Related to Autistic Traits and Behavioral Problems in Typically Developing Children and Those With Autism Spectrum Disorders.

Front Hum Neurosci 2018 21;12:518. Epub 2018 Dec 21.

National Center of Neurology and Psychiatry, Department of Preventive Intervention for Psychiatric Disorders, National Institute of Mental Health, Tokyo, Japan.

An important objective for researchers and clinicians is to gain a better understanding of the factors that underlie autism spectrum disorders (ASDs). It is possible that investigating objective and quantitative behavioral phenotypes and their relationship to clinical characteristics, such as autistic traits and other emotional/behavioral problems, might facilitate this process. Given this, in the current study we examined the link between locomotor dynamics and clinical characteristics, including autistic traits and emotional/behavioral problems, in children with ASD ( = 14) and typically developing (TD) children ( = 13). A watch-type actigraph was used to continuously measure locomotor activity which was assessed in terms of mean activity levels and the skewness of activity. Parents assessed quantitative autistic traits using the Japanese version of the Social Responsiveness Scale (SRS) and emotional and behavioral problems using the Japanese version of the Strengths and Difficulties Questionnaire (SDQ). Results showed that among all children, all-day activity was more negatively skewed, suggesting sporadic large all-day "troughs" in activity and was significantly correlated with the SRS social awareness subscale score ( = -0.446, = 0.038). In addition, the more negatively skewed daytime locomotor activity was associated with the SDQ Hyperactivity Inattention subscale score ( = -0.493, = 0.020). The results of this study indicate that investigating locomotor dynamics may provide one way to increase understanding of the neurophysiological mechanisms underlying the clinical characteristics of ASD.
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http://dx.doi.org/10.3389/fnhum.2018.00518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308199PMC
December 2018

Neural correlates of body comparison and weight estimation in weight-recovered anorexia nervosa: a functional magnetic resonance imaging study.

Biopsychosoc Med 2018 31;12:15. Epub 2018 Oct 31.

9School of Health Sciences Fukuoka, International University of Health and Welfare, Fukuoka, 831-8501 Japan.

Background: The neural mechanisms underlying body dissatisfaction and emotional problems evoked by social comparisons in patients with anorexia nervosa (AN) are currently unclear. Here, we elucidate patterns of brain activation among recovered patients with AN (recAN) during body comparison and weight estimation with functional magnetic resonance imaging (fMRI).

Methods: We used fMRI to examine 12 patients with recAN and 13 healthy controls while they performed body comparison and weight estimation tasks with images of underweight, healthy weight, and overweight female bodies. In the body comparison task, participants rated their anxiety levels while comparing their own body with the presented image. In the weight estimation task, participants estimated the weight of the body in the presented image. We used between-group region of interest (ROI) analyses of the blood oxygen level dependent (BOLD) signal to analyze differences in brain activation patterns between the groups. In addition, to investigate activation outside predetermined ROIs, we performed an exploratory whole-brain analysis to identify group differences.

Results: We found that, compared to healthy controls, patients with recAN exhibited significantly greater activation in the pregenual anterior cingulate cortex (pgACC) when comparing their own bodies with images of underweight female bodies. In addition, we found that, compared with healthy controls, patients with recAN exhibited significantly smaller activation in the middle temporal gyrus corresponding to the extrastriate body area (EBA) when comparing their own bodies, irrespective of weight, during self-other comparisons of body shape.

Conclusions: Our findings from a group of patients with recAN suggest that the pathology of AN may lie in an inability to regulate negative affect in response to body images via pgACC activation during body comparisons. The findings also suggest that altered body image processing in the brain persists even after recovery from AN.
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http://dx.doi.org/10.1186/s13030-018-0134-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208027PMC
October 2018

Acoustic Hyper-Reactivity and Negatively Skewed Locomotor Activity in Children With Autism Spectrum Disorders: An Exploratory Study.

Front Psychiatry 2018 6;9:355. Epub 2018 Aug 6.

Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan.

Investigation of objective and quantitative behavioral phenotypes along with neurobiological endophenotypes might lead to increased knowledge of the mechanisms that underlie autism spectrum disorders (ASD). Here, we investigated the association between locomotor dynamics and characteristics of the acoustic startle response (ASR) and its modulation in ASD ( = 14) and typically developing (TD, = 13) children. The ASR was recorded in response to acoustic stimuli in increments of 10 dB (65-105 dB SPL). We calculated the average ASR magnitude for each stimulus intensity and peak-ASR latency. Locomotor activity was continuously measured with a watch-type actigraph. We examined statistics of locomotor activity, such as mean activity levels and the skewness of activity. Children with ASD had a significantly greater ASR magnitude in response to a weak acoustic stimulus, which reflects acoustic hyper-reactivity. The skewness of all-day activity was significantly more negative in children with ASD than those with TD. Skewness of daytime activity was also more negative, although only of borderline statistical significance. For all children, the higher mean and more negatively skewed daytime activity, reflecting hyperactivity that was associated with sporadic large daytime "troughs," was significantly correlated with acoustic hyper-reactivity. The more negatively skewed locomotor activity occurring in the daytime was also associated with impaired sensorimotor gating, examined as prepulse inhibition at a prepulse intensity of 70 dB. This comprehensive investigation of locomotor dynamics and the ASR extends our understanding of the neurophysiology that underlies ASD.
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http://dx.doi.org/10.3389/fpsyt.2018.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088201PMC
August 2018

Correction to: Purging behaviors relate to impaired subjective sleep quality in female patients with anorexia nervosa: a prospective observational study.

Biopsychosoc Med 2018 15;12. Epub 2018 Mar 15.

1Department of Psychosomatic Medicine, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516 Japan.

[This corrects the article DOI: 10.1186/s13030-017-0107-7.].
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http://dx.doi.org/10.1186/s13030-018-0124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856280PMC
March 2018

Purging behaviors relate to impaired subjective sleep quality in female patients with anorexia nervosa: a prospective observational study.

Biopsychosoc Med 2017 16;11:22. Epub 2017 Aug 16.

Department of Psychosomatic Medicine, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516 Japan.

Background: We examined how purging behaviors relate to subjective sleep quality and sleep patterns and how symptoms of disordered eating behaviors relate to global sleep quality in female patients with anorexia nervosa (AN).

Methods: Participants were new consecutive female inpatients with a primary diagnosis of AN admitted to the Department of Psychosomatic Medicine at Kohnodai Hospital between June 26 and December 25, 2015. We recorded patients' habitual eating behaviors, laxative overuse, or uretic misuse, and administered the Japanese versions of the Pittsburgh Sleep Quality Index (PSQI-J) and Center for Epidemiologic Studies Depression Scale. Raw PSQI-J data were used to determine sleep patterns (sleep-onset time, wake-up time, and sleep duration). To examine how purging behaviors related to sleep quality, we compared variables between AN restricting type (ANr) and AN binge-eating/purging type (ANbp). Spearman's rank correlation analysis was used to examine which potential factors influence global PSQI-J score.

Results: Participants were 20 patients, of whom 12 had ANbp. Two ANr patients (25%) had global PSQI-J scores greater than 5, compared to 9 ANbp patients (75%;  < 0.05). Circadian rhythm disruption and abnormal sleep duration were significantly greater in ANbp patients than in ANr patients ( < 0.05). Global PSQI-J was significantly correlated with a diagnosis of ANbp ( = 0.525;  < 0.05), vomiting ( = 0.561;  < 0.05), and duration of illness ( = 0.536;  < 0.05).

Conclusions: ANbp patients had worse global sleep quality and greater disrupted sleep than did ANr patients. This suggests that treatments focusing on sleep would be useful, especially for ANbp patients. Furthermore, vomiting and duration of illness should be considered essential factors related to impaired global sleep quality.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s13030-017-0107-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558764PMC
August 2017

Influence of psychological factors on acute exacerbation of tension-type headache: Investigation by ecological momentary assessment.

J Psychosom Res 2015 Sep 16;79(3):239-42. Epub 2015 Jul 16.

Educational Physiology Laboratory, Graduate School of Education, The University of Tokyo, Tokyo, Japan.

Objective: In this study, we investigated whether psychological factors were associated with subsequent acute exacerbation of tension-type headache (TTH) in a prospective and ecologically valid manner with computerized ecological momentary assessment.

Methods: Eighteen women and five men with TTH wore watch-type computers that acted as an electronic diary for 1week. The subjects recorded momentary headache intensity, psychological stress, anxiety, and depressive mood with a visual analog scale of 0-100 approximately every 6h as well as when waking up, when going to bed, and at acute headache exacerbations. Multilevel logistic regression analysis with acute headache exacerbation occurrence as the outcome was conducted. Person-mean centering was applied to psychological factors to disaggregate between- and within-individual association.

Results: Momentary psychological stress was associated with subsequent increase in headache exacerbation within 3h [Odds Ratio (95% CI)=1.32 (1.07, 1.64) for 10-point increments] while the individual mean of psychological stress was not.

Conclusion: These results support the possibility that psychological stress could trigger acute exacerbations of TTH.
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http://dx.doi.org/10.1016/j.jpsychores.2015.06.008DOI Listing
September 2015

Development of an ecological momentary assessment scale for appetite.

Biopsychosoc Med 2015 15;9(1). Epub 2015 Jan 15.

Educational Physiology Laboratory, Graduate School of Education, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 Japan.

Background: An understanding of eating behaviors is an important element of health education and treatment in clinical populations. To understand the biopsychosocial profile of eating behaviors in an ecologically valid way, ecological momentary assessment (EMA) is appropriate because its use is able to overcome the recall bias in patient-reported outcomes (PROs). As appetite is a key PRO associated with eating behaviors, this study was done to develop an EMA scale to evaluate the within-individual variation of momentary appetite and uses this scale to discuss the relationships between appetite and various psychological factors.

Methods: Twenty healthy participants (age 23.6 ± 4.2 years old) wore a watch-type computer for a week. Several times a day, including just before and after meals, they recorded their momentary psychological stress, mood states, and ten items related to appetite. In addition, they recorded everything they ate and drank into a personal digital assistant (PDA)-based food diary. Multilevel factor analysis was used to investigate the factor structure of the scale, and the reliability and validity of the scale were also explored.

Results: Multilevel factor analyses found two factors at the within-individual level (hunger/fullness and cravings) and one factor at the between-individual level. Medians for the individually calculated Cronbach's alphas were 0.89 for hunger/fullness, 0.71 for cravings, and 0.86 for total appetite (the sum of all items). Hunger/fullness, cravings, and total appetite all decreased significantly after meals compared with those before meals, and hunger/fullness, cravings, and total appetite before meals were positively associated with energy intake. There were significant negative associations between both hunger/fullness and total appetite and anxiety and depression as well as between cravings, and depression, anxiety and stress.

Conclusions: The within-individual reliability of the EMA scale to assess momentary appetite was confirmed in most subjects and it was also validated as a useful tool to understand eating behaviors in daily settings. Further refinement of the scale is necessary and further investigations need to be conducted, particularly on clinical populations.
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http://dx.doi.org/10.1186/s13030-014-0029-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302437PMC
January 2015

Association of the c.385C>A (p.Pro129Thr) polymorphism of the fatty acid amide hydrolase gene with anorexia nervosa in the Japanese population.

Mol Genet Genomic Med 2014 Jul 24;2(4):313-8. Epub 2014 Feb 24.

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry Kodaira, Tokyo, Japan ; School of Health Sciences at Fukuoka, International University of Health and Welfare Ohkawa, Japan.

The functional c.385C>A single-nucleotide polymorphism (SNP) in the fatty acid amide hydrolase (FAAH) gene, one of the major degrading enzymes of endocannabinoids, is reportedly associated with anorexia nervosa (AN). We genotyped the c.385C>A SNP (rs324420) in 762 lifetime AN and 605 control participants in Japan. There were significant differences in the genotype and allele frequencies of c.385C>A between the AN and control groups. The minor 385A allele was less frequent in the AN participants than in the controls (allele-wise, odds ratio = 0.799, 95% confidence interval [CI] 0.653-0.976, P = 0.028). When the cases were subdivided into lifetime restricting subtype AN and AN with a history of binge eating or purging, only the restricting AN group exhibited a significant association (allele-wise, odds ratio = 0.717, 95% CI 0.557-0.922, P = 0.0094). Our results suggest that having the minor 385A allele of the FAAH gene may be protective against AN, especially restricting AN. This finding supports the possible role of the endocannabinoid system in susceptibility to AN.
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http://dx.doi.org/10.1002/mgg3.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113271PMC
July 2014

Ghrelin gene variants and eating disorders.

Authors:
Tetsuya Ando

Vitam Horm 2013 ;92:107-23

Section of Stress Research, Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Genetic factors have been implicated in playing a significant role in susceptibility to eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). Genetic variants of ghrelin, an endogenous acylated peptide that stimulates growth hormone secretion, enhances appetite, and increases body weight, have been investigated in association with eating disorders, as changes in the ghrelin/growth hormone secretagogue receptor (GHSR)/ghrelin O-acyltransferase (GOAT) system have been implicated in its pathology. Although most candidate-gene association studies have not been able to identify ghrelin gene variants as being significantly associated with either AN or BN, some ghrelin variants may be associated with BN in Japanese. Furthermore, a significant association of a GHSR gene variant with BN and that of a GOAT gene variant with AN have been found. However, there have been relatively few studies, tested variants are restricted, and sample sizes are often modest. Therefore, further studies are needed to elucidate the role of ghrelin-related gene variants in the predisposition and pathology of eating disorders.
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http://dx.doi.org/10.1016/B978-0-12-410473-0.00004-0DOI Listing
December 2013

No association of brain-derived neurotrophic factor Val66Met polymorphism with anorexia nervosa in Japanese.

Am J Med Genet B Neuropsychiatr Genet 2012 Jan 29;159B(1):48-52. Epub 2011 Nov 29.

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

The Met66 allele of the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has been reported to be associated with anorexia nervosa (AN), and also lower minimum body mass index (BMI) and higher harm avoidance in AN. We genotyped the Val66Met polymorphism (rs6265) in 689 AN cases and 573 control subjects. There were no significant differences in the genotype or allele frequencies of the Val66Met between AN and control subjects (allele wise, odds ratio = 0.920, 95% CI 0.785-1.079, P = 0.305). No difference was found in minimum BMIs related to Val66Met in AN (one-way ANOVA, P > 0.05). Harm avoidance scores on the Temperament and Character Inventory were lower in the Met66 allele carriers (P = 0.0074) contrary to the previous report. Thus we were unable to replicate the previous findings that the Met66 allele of the BDNF is associated with AN and that the minimum BMI is lower or the harm avoidance score is higher in AN patients with the Met66 allele.
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http://dx.doi.org/10.1002/ajmg.b.32000DOI Listing
January 2012

Functional polymorphism in the GPR55 gene is associated with anorexia nervosa.

Synapse 2011 Feb;65(2):103-8

Department of Psychiatry, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.

Endocannabinoids, anandamide, and 2-arachidonoyl glycerol are involved in food intake and appetite. Although anandamide is now thought to be a ligand for vanilloid receptor, receptors that are targets of anandamide could play a similar role in eating behaviors and related disorders. This study therefore focused on the receptor, which is called G-protein-coupled receptor 55 (GPR55) that had recently been reported to have binding affinity for endocannabinoids. Functional analysis of the sole missense polymorphism, rs3749073 (Gly195Val) in the GPR55 gene was performed by detecting the phosphorylation level of extracellular signal-regulated kinase (ERK) in Chinese-Hamster-Ovary (CHO) cells engineered to express human GPR55. Val195 type GPR55 appeared to induce less phosphorylated ERK than Gly195 type GPR55 when CHO cells were treated with anandamide and lysophosphatidylinositol (LPI). An association between the functional Gly195Val polymorphism and anorexia nervosa was tested in a female Japanese population comprising 235 patients and 1244 controls. The Val195 allele and homozygote of the Val195 allele were more abundant in the group of patients diagnosed with anorexia nervosa (P = 0.023, Odds ratio = 1.31 (95% Cl = 1.03-1.37), P = 0.0048, OR = 2.41 (95% Cl = 1.34-4.34), respectively). In conclusion, the low-functioning Val195 allele of GPR55 appears to be a risk factor for anorexia nervosa.
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http://dx.doi.org/10.1002/syn.20821DOI Listing
February 2011

A ghrelin gene variant may predict crossover rate from restricting-type anorexia nervosa to other phenotypes of eating disorders: a retrospective survival analysis.

Psychiatr Genet 2010 Aug;20(4):153-9

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Background: Patients with anorexia nervosa restricting type (AN-R) often develop bulimic symptoms and crossover to AN-binge eating/purging type (AN-BP), or to bulimia nervosa (BN). We have reported earlier that genetic variants of an orexigenic peptide ghrelin are associated with BN. Here, the relationship between a ghrelin gene variant and the rate of change from AN-R to other phenotypes of eating disorders (EDs) was investigated.

Methods: Participants were 165 patients with ED, initially diagnosed as AN-R. The dates of their AN-R onset and changes in diagnosis to other subtypes of ED were investigated retrospectively. Ghrelin gene 3056 T-->C SNP (single nucleotide polymorphism) was genotyped. Probability and hazard ratios were analyzed using life table analysis and Cox's proportional hazard regression model, in which the starting point was the time of AN-R onset and the outcome events were the time of (i) onset of binge eating, that is, when patients changed to binge eating AN and BN and (ii) recovery of normal weight, that is, when patients changed to BN or remission.

Results: Patients with the TT genotype at 3056 T-->C had a higher probability and hazard ratio for recovery of normal weight. The ghrelin SNP was not related with the onset of binge eating.

Conclusion: The 3056 T-->C SNP of the ghrelin gene is related to the probability and the rate of recovery of normal body weight from restricting-type AN.
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http://dx.doi.org/10.1097/YPG.0b013e32833a1f0eDOI Listing
August 2010

Identification of novel candidate loci for anorexia nervosa at 1q41 and 11q22 in Japanese by a genome-wide association analysis with microsatellite markers.

J Hum Genet 2009 Sep 14;54(9):531-7. Epub 2009 Aug 14.

Department of Pathology, Research Institute, International Medical Center of Japan, Shinjuku, Tokyo, Japan.

The Japanese Genetic Research Group for Eating Disorders (JGRED) is a multisite collaborative study group that was organized for the systematic recruitment of patients with an eating disorder for the purpose of genetic study in Japan. We conducted a genome-wide case-control association study using 23 465 highly polymorphic microsatellite (MS) markers to identify genomic loci related to anorexia nervosa (AN). Pooled DNA typing in two screening stages, followed by individual typing of 320 AN cases and 341 controls, allowed us to identify 10 MS markers to be associated with AN. To narrow down genomic regions responsible for the association of these MS markers, we further conducted a single-nucleotide polymorphism (SNP) association analysis for 7 of the 10 loci in 331 AN cases and 872 controls, which include the 320 AN cases and the 341 controls genotyped in the MS screening, respectively. Two loci, namely 1q41 and 11q22, remained significantly associated with AN in the SNP-based fine mapping, indicating the success in narrowing down susceptibility regions for AN. Neither of these loci showed a positive evidence of association with bulimia nervosa. The most significant association was observed at SNP rs2048332 (allelic P-value=0.00023) located at 3'-downstream of the SPATA17 gene on the 1q41 locus. The association analysis for MS-SNP haplotypes detected a statistically significant association (permutation P-value=0.00003) of the A-4-G-T haplotype that comprised four SNP/MS markers (rs6590474-D11S0268i-rs737582-rs7947224) on the 11q22 locus with AN. This linkage disequilibrium block spanning a 20.2-kb interval contains exon 9 of the CNTN5 gene encoding contactin 5.
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http://dx.doi.org/10.1038/jhg.2009.74DOI Listing
September 2009

Psychological and weight-related characteristics of patients with anorexia nervosa-restricting type who later develop bulimia nervosa.

Biopsychosoc Med 2008 Feb 12;2. Epub 2008 Feb 12.

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira-shi, Tokyo 187-8553, Japan.

Background: Patients with anorexia nervosa-restricting type (AN-R) sometimes develop accompanying bulimic symptoms or the full syndrome of bulimia nervosa (BN). If clinicians could predict who might change into the bulimic sub-type or BN, preventative steps could be taken. Therefore, we investigated anthropometric and psychological factors possibly associated with such changes.

Method: All participants were from a study by the Japanese Genetic Research Group for Eating Disorders. Of 80 patients initially diagnosed with AN-R, 22 changed to the AN-Binge Eating/Purging Type (AN-BP) and 14 to BN for some period of time. The remaining 44 patients remained AN-R only from the onset to the investigation period. Variables compared by ANOVA included anthropometric measures, personality traits such as Multiple Perfectionism Scale scores and Temperament and Character Inventory scores, and Beck Depression Inventory-II scores.

Results: In comparison with AN-R only patients, those who developed BN had significantly higher current BMI (p < 0.05) and maximum BMI in the past (p < 0.05). They also scored significantly higher for the psychological characteristic of parental criticism (p < 0.05) and lower in self-directedness (p < 0.05), which confirms previous reports, but these differences disappeared when the depression score was used as a co-variant. No significant differences were obtained for personality traits or depression among the AN-R only patients irrespective of their duration of illness.

Conclusion: The present findings suggest a tendency toward obesity among patients who cross over from AN-R to BN. Low self-directedness and high parental criticism may be associated with the development of BN by patients with AN-R, although the differences may also be associated with depression.
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http://dx.doi.org/10.1186/1751-0759-2-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275291PMC
February 2008

Variations in the preproghrelin gene correlate with higher body mass index, fat mass, and body dissatisfaction in young Japanese women.

Am J Clin Nutr 2007 Jul;86(1):25-32

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Background: Ghrelin is an endogenous peptide that stimulates growth hormone secretion, enhances appetite, and increases body weight and may play a role in eating disorders.

Objective: The purpose was to determine whether any preproghrelin gene variants are associated with anthropometric measures, circulating ghrelin, lipid concentrations, insulin resistance, or psychological measures relevant to eating disorders in young women.

Design: This cross-sectional study compared outcome measures between preproghrelin genotypes. The participants in the study included 264 Japanese women [university students with a mean (+/-SD) age of 20.4 +/- 0.7] with no history of eating disorders. The main outcomes were responses to the Eating Disorder Inventory-2 (EDI-2), anthropometric measures, measures of depression and anxiety, and fasting blood concentrations of acylated or desacyl ghrelin, lipids, glucose, and insulin.

Results: Two single nucleotide polymorphisms (SNPs) whose minor allele frequencies were >0.05--the Leu72Met (408 C-->A) SNP in exon 2 and the 3056 T-->C SNP in intron 2--were used for association analysis. The 3056C allele was significantly associated with a higher acylated ghrelin concentration (P=0.0021), body weight (P=0.011), body mass index (P=0.007), fat mass (P=0.012), waist circumference (P=0.008), and skinfold thickness (P=0.011) and a lower HDL-cholesterol concentration (P=0.02). Interestingly, the 3056C allele was related to elevated scores in the Drive for Thinness-Body Dissatisfaction (DT-BD) subscale of the EDI-2 (P=0.003).

Conclusion: Our findings suggest that the preproghrelin gene 3056T-->C SNP is associated with changes in basal ghrelin concentrations and physical and psychological variables related to eating disorders and obesity.
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http://dx.doi.org/10.1093/ajcn/86.1.25DOI Listing
July 2007

Possible role of preproghrelin gene polymorphisms in susceptibility to bulimia nervosa.

Am J Med Genet B Neuropsychiatr Genet 2006 Dec;141B(8):929-34

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Previous investigations have suggested that ghrelin, an endogenous orexigenic peptide, is involved in the pathology of eating disorders. We conducted a study to determine whether any preproghrelin gene polymorphisms are associated with eating disorders. Three hundred thirty-six eating disorder patients, including 131 anorexia nervosa (AN)-restricting types (AN-R), 97 AN-binge eating/purging types (AN-BP) and 108 bulimia nervosa (BN)-purging types (BN-P), and 300 healthy control subjects participated in the study. Genotyping was performed to determine the polymorphisms present, and with this information, linkage disequilibrium (LD) between the markers was analyzed and the distributions of the genotypes, the allele frequencies, and the haplotype frequencies were compared between the groups. The Leu72Met (408 C > A) (rs696217) polymorphism in exon 2 and the 3056 T > C (rs2075356) polymorphism in intron 2 were in LD (D' = 0.902, r2 = 0.454). Both polymorphisms were significantly associated with BN-P (allele-wise: P = 0.0410, odds ratio (OR) = 1.48; P = 0.0035, OR = 1.63, for Leu72Met and 3056 T > C, respectively). In addition, we observed a significant increase in the frequency of the haplotype Met72-3056C in BN-P patients (P = 0.0059, OR = 1.71). Our findings suggest that the Leu72Met (408 C > A) and the 3056 T > C polymorphisms of the preproghrelin gene are associated with susceptibility to BN-P.
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http://dx.doi.org/10.1002/ajmg.b.30387DOI Listing
December 2006

Development and validation of the psychosomatic scale for atopic dermatitis in adults.

J Dermatol 2006 Jul;33(7):439-50

Department of Psychosomatic Research, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Psychosocial factors play an important role in the course of adult atopic dermatitis (AD). Nevertheless, AD patients are rarely treated for their psychosomatic concerns. The purpose of the present study was to develop and validate a brief self-rating scale for adult AD in order to aid dermatologists in evaluating psychosocial factors during the course of AD. A preliminary scale assessing stress-induced exacerbation, the secondary psychosocial burden, and attitude toward treatment was developed and administered to 187 AD patients (82 male, 105 female, aged 28.4 +/- 7.8, 13-61). Severity of skin lesions and improvement with standard dermatological treatment were assessed by both the dermatologist and the participant. Measures of anxiety and depression were also determined. In addition, psychosomatic evaluations were made according to the Psychosomatic Diagnostic Criteria for AD. Factor analysis resulted in the development of a 12-item scale (The Psychosomatic Scale for Atopic Dermatitis; PSS-AD) consisting of three factors: (i) exacerbation triggered by stress; (ii) disturbances due to AD; and (iii) ineffective control. Internal consistency indicated by Cronbach's alpha coefficient was 0.86 for the entire measure, 0.82 for (i), 0.81 for (ii), and 0.77 for (iii), verifying the acceptable reliability of PSS-AD. Patients with psychosomatic problems had higher PSS-AD scores than those without. PSS-AD scores were positively associated with the severity of the skin lesions, anxiety and depression. The scores were negatively associated with improvement during dermatological treatments. In conclusion, PSS-AD is a simple and reliable measure of the psychosomatic pathology of adult AD patients. It may be useful in dermatological practice for screening patients who would benefit from psychological or psychiatric interventions.
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http://dx.doi.org/10.1111/j.1346-8138.2006.00107.xDOI Listing
July 2006

Uncoupling protein-2/uncoupling protein-3 gene polymorphism is not associated with anorexia nervosa.

Psychiatr Genet 2004 Dec;14(4):215-8

Division of Psychosomatic Research, National Institute of Mental Health, Kohnodai Hospital, National Center of Neurology and Psychiatry, Ichikawa, Chiba, Japan.

Energy expenditure abnormalities have been observed in anorexia nervosa (AN). The uncoupling proteins (UCPs) have been implicated as having a role in energy metabolism and thermogenesis, and an association between a marker flanking the UCP-2/UCP-3 gene cluster and AN has been reported. Also known are insertion/deletion and -866G/A polymorphisms in the UCP-2 gene, and the -55C/T polymorphism in the UCP-3 gene. Differences in these alleles are reportedly related to changes in energy expenditure, body mass index, fat tissue accumulation and obesity. Therefore, this case-control association analysis was done to determine whether any of these UCP-2/3 gene polymorphisms are related to a predisposition to AN. In analysis of a cohort of 106 female Japanese AN sufferers and 126 normal female controls, we found no between-group differences in the polymorphism frequencies of these groups. The hypothesis that differences in the UCP-2/3 gene influence the susceptibility to AN was not supported.
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http://dx.doi.org/10.1097/00041444-200412000-00009DOI Listing
December 2004

HPA axis activation and neurochemical responses to bacterial translocation from the gastrointestinal tract.

Ann N Y Acad Sci 2003 May;992:21-9

Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.

Stress can cause migration of indigenous bacterial flora from the gut to the peritoneum, a phenomenon known as bacterial translocation. Destruction of the cell walls of gram-negative bacteria can result in the production of endotoxin (lipopolysaccharide, LPS), which is the likely cause of sepsis. Exogenously administered LPS can activate the hypothalamo-pituitary-adrenal (HPA) axis as well as brain noradrenergic and indoleaminergic systems. Thus, it is possible that activations of these systems associated with laboratory stressors in rats and mice could be attributed to bacterial translocation and LPS production. To test this hypothesis we conducted experiments on the time course of bacterial translocation in response to restraint in mice, while measuring HPA and neurochemical responses. These experiments failed to show good correlations between the occurrence of bacterial translocation and HPA and neurochemical activations, suggesting that the later responses were not linked to bacterial translocation. This conclusion was supported by the observation of normal neurochemical responses to restraint in germ-free mice. In further experiments, translocation of Salmonella typhimurium, a bacterium that readily translocates in unstressed animals, was associated with HPA activation and noradrenergic and indoleaminergic responses, indicating that bacterial translocation can indeed activate the HPA axis and brain amines. However, the above experiments suggest that this is not the mechanism by which restraint activates these systems.
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http://dx.doi.org/10.1111/j.1749-6632.2003.tb03134.xDOI Listing
May 2003