Publications by authors named "Ichiro Kusumi"

172 Publications

Lipid and Energy Metabolism of the Gut Microbiota Is Associated with the Response to Probiotic Strain for Anxiety and Depressive Symptoms in Schizophrenia.

J Pers Med 2021 Sep 30;11(10). Epub 2021 Sep 30.

Division of Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, Tokyo 104-0045, Japan.

A recent meta-analysis found that probiotics have moderate-to-large beneficial effects on depressive symptoms in patients with psychiatric disorders. However, it remains unclear how the baseline gut microbiota before probiotic administration influences the host's response to probiotics. Therefore, we aimed to determine whether the predicted functional profile of the gut microbiota influences the effectiveness of probiotic treatment in patients with schizophrenia. A total of 29 patients with schizophrenia consumed A-1 (synonym MCC1274) for 4 weeks. We considered patients who showed a 25% or more reduction in the Hospital Anxiety and Depression Scale total score at 4 weeks from baseline to be "responders" and those who did not to be "non-responders". We predicted the gut microbial functional genes based on 16S rRNA gene sequences and applied the linear discriminant analysis effect size method to determine the gut microbial functional genes most likely to explain the differences between responders and non-responders at baseline. The results showed that lipid and energy metabolism was elevated at baseline in responders ( = 12) compared to non-responders ( = 17). These findings highlight the importance of assessing the gut microbial functional genes at baseline before probiotic therapy initiation in patients with psychiatric disorders.
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http://dx.doi.org/10.3390/jpm11100987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539730PMC
September 2021

The type rather than the daily dose or number of antipsychotics affects the incidence of hyperglycemic progression.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Oct 9;113:110453. Epub 2021 Oct 9.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo 060-8638, Japan. Electronic address:

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H, M, M, and 5-HT receptors, the incidence of hyperglycemic progression was higher in the medium- and high-daily dose groups than in the low-daily dose group in the antipsychotic group with strong blockade of these receptors. Our study indicated that the type of antipsychotic had a greater affect on the incidence of hyperglycemic progression than the daily dose of antipsychotics or their number. Among these, zotepine was most likely to increase the incidence of hyperglycemic progression, suggesting the need for caution when these antipsychotics are prescribed.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110453DOI Listing
October 2021

Subjective cognitive impairment and presenteeism mediate the associations of rumination with subjective well-being and ill-being in Japanese adult workers from the community.

Biopsychosoc Med 2021 Oct 2;15(1):15. Epub 2021 Oct 2.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-8638, Japan.

Background: In recent years, the roles of rumination, subjective cognitive impairment (SCI), and presenteeism have been emphasized in occupational mental health. However, associations between rumination, SCI, presenteeism, and psychological well-being are not fully understood. We hypothesized that SCI and presenteeism mediate the associations between rumination and subjective well-being (SWB) and subjective ill-being (SIB). Hence, we investigated the mediating roles of SCI and presenteeism in this study.

Methods: A total of 458 adult workers (mean age, 40.8±11.9 years; 44.1% male), who were recruited in Tokyo using convenience sampling, were analyzed in this study. The Ruminative Responses Scale, Cognitive Complaints in Bipolar Disorder Rating Assessment, Work Limitations Questionnaire 8, and Subjective Well-being Inventory were used to evaluate rumination, SCI, presenteeism, and psychological well-being (SWB and SIB), respectively. Path analyses were performed to evaluate the relations between these parameters.

Results: The path analysis indicated that rumination, SCI, and presenteeism were directly and negatively associated with SWB and SIB. Regarding indirect effects, rumination was negatively associated with SWB and SIB via SCI, presenteeism, and both SCI and presenteeism. Furthermore, SCI was negatively associated with SWB and SIB via presenteeism.

Conclusions: The results suggest that SCI and presenteeism mediate the associations of rumination with SWB and SIB in Japanese adult workers. To address the psychological well-being associated with rumination, evaluating SCI and presenteeism simultaneously may be useful in occupational mental health. This study provides key insights into the development of comprehensive intervention strategy based on the biopsychosocial perspective for worker's psychological well-being.
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http://dx.doi.org/10.1186/s13030-021-00218-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487485PMC
October 2021

Associations of Cognitive Complaints and Depressive Symptoms with Health-Related Quality of Life and Perceived Overall Health in Japanese Adult Volunteers.

Int J Environ Res Public Health 2021 Sep 13;18(18). Epub 2021 Sep 13.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.

Cognitive complaints, defined as perceived cognitive dysfunction in daily living, are associated with depressive symptoms. The associations of cognitive complaints and depressive symptoms with health-related quality of life (HRQoL) and perceived overall health in Japanese adults remains unknown. To investigate these relationships, we evaluated a convenience sample of 525 Japanese adult volunteers (Mage: 41.3 ± 11.7; 238 male and 287 female). We used the Cognitive Complaints in Bipolar Disorder Rating Assessment (evaluating cognitive complaints), Patient Health Questionnaire-9 (evaluating depressive symptoms), EuroQol-5 Dimension-5 Level (EQ-5D-5L; evaluating HRQoL), and EuroQol-Visual Analogue Scale (EQ-VAS; evaluating perceived overall health). Our path analyses suggested that both cognitive complaints and depressive symptoms had significant total effects on HRQoL and perceived overall health. Furthermore, cognitive complaints were not significantly associated directly with HRQoL and perceived overall health, whereas cognitive complaints were significantly associated with HRQoL and perceived overall health indirectly via depressive symptoms. Depressive symptoms were significantly associated directly with HRQoL and perceived overall health. This study suggests that depressive symptoms may mediate the associations of cognitive complaints with HRQoL and perceived overall health. Thus, to address the HRQoL and perceived overall health associated with cognitive complaints, evaluation and intervention for depressive symptoms may be useful in public health.
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http://dx.doi.org/10.3390/ijerph18189647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468755PMC
September 2021

Predictors of social anxiety disorder with major depressive episodes among Japanese university students.

PLoS One 2021 27;16(9):e0257793. Epub 2021 Sep 27.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Background: Social anxiety disorder (SAD) develops in the early teens and is a common disorder among university students. Understanding the predictive factors of SAD comorbid with major depressive episode (MDE) is important for student mental health care. The aim of this study was to identify the personality traits that predict SAD with MDE by analyzing longitudinal data of Japanese university students.

Methods: In this retrospective study, Japanese university students who visited the health care center of Hokkaido University for the first time were divided into the following four groups: "Control" (n = 43), "MDE" (n = 16), "SAD" (n = 28), and "SAD with MDE" (n = 61) based on the Patient Health Questionnaire-9 (PHQ-9), the Liebowitz Social Anxiety Scale, and core anxiety symptoms for SAD in the Mini International Neuropsychiatric Interview during screening. Predictors for SAD with MDE were identified by a four-group comparison of the Temperament and Character Inventory and PHQ-9 data previously obtained at the enrollment using analysis of variance and post-hoc tests.

Results: Upon comparing the four groups using analysis of variance, there were significant differences in the baseline PHQ-9 summary score, Harm-Avoidance (HA), and Self-Directedness (SD). According to results of the post-hoc test, all three showed a significant difference between the "Control" and "SAD with MDE." Furthermore, there was a significant difference in HA scores between "SAD" and "Control." In all the groups, the mean time from enrollment to the first visit to the center was >2 years.

Conclusion: A higher HA score at baseline is a predictor of SAD with or without MDE. Higher PHQ-9 summary and lower SD scores at baseline are predictive factors of SAD with MDE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476026PMC
September 2021

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Sci Rep 2021 09 8;11(1):17823. Epub 2021 Sep 8.

Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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http://dx.doi.org/10.1038/s41598-021-97140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426488PMC
September 2021

Interpersonal Sensitivity Mediates the Effects of Childhood Maltreatment on the Evaluation of Life Events and Anxiety States in Adult Community Volunteers.

Neuropsychiatr Dis Treat 2021 20;17:2757-2766. Epub 2021 Aug 20.

Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, 160-0023, Japan.

Background: Childhood maltreatment has long-lasting psychological effects, which often manifest in adulthood. Previous studies have suggested that the effects of childhood maltreatment are not only direct but also indirect, being mediated by other factors. In this study, we hypothesized that the effects of childhood maltreatment on state anxiety in adulthood are mediated by interpersonal sensitivity and the evaluation of life events, and investigated this possibility by covariance structure analysis.

Subjects And Methods: Self-administered questionnaires (Child Abuse and Trauma Scale, State-Trait Anxiety Inventory Form Y, Life Experiences Survey, and Interpersonal Sensitivity Measure) were distributed to adult community volunteers in Japan, and 404 eligible responses were collected. A structural equation model was constructed to analyze the direct and indirect effects of childhood maltreatment on state anxiety, with interpersonal sensitivity and the evaluation of life events as potential mediators.

Results: Our model showed that childhood maltreatment increases state anxiety in adulthood both directly and indirectly via interpersonal sensitivity. In addition, interpersonal sensitivity mediated the effects of childhood maltreatment on the negative evaluation of life events, and the negative evaluation of life events mediated the effects of interpersonal sensitivity on anxiety symptoms.

Limitations: There may be possible recall bias owing to the self-administration of the questionnaire. In addition, this study had a cross-sectional design, and hence the results should be validated by a prospective study.

Conclusion: The effects of childhood maltreatment on the state anxiety of adult volunteers are not only direct but are also mediated by interpersonal sensitivity. Our results suggest that assessing interpersonal sensitivity may help to determine optimal treatments for patients with anxiety who experienced maltreatment in childhood.
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http://dx.doi.org/10.2147/NDT.S310010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384342PMC
August 2021

The relationship among sleep reactivity, job-related stress, and subjective cognitive dysfunction: a cross-sectional study using path analysis.

Ind Health 2021 Sep 14;59(4):229-238. Epub 2021 Jul 14.

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

Insomnia, job-related stress, and cognitive dysfunction affect the mental health of workers. However, the relationships among sleep reactivity, job-related stress, and subjective cognitive dysfunction in workers remains not fully understood. Therefore, this study seeks to investigate the relationships among these variables in Japanese adult workers. In total, 536 adult workers in Japan were evaluated using the Japanese version of Ford Insomnia Response to Stress Test, Brief Job Stress Questionnaire, and Cognitive Complaints in Bipolar Disorder Rating Assessment to assess sleep reactivity, job-related stress, and subjective cognitive function, respectively. Path analysis was also carried out. The results of the path analysis showed that sleep reactivity significantly influenced on subjective cognitive dysfunction directly and indirectly via job stressors and stress reaction. Our results may not be generalizable to underage workers because only adult workers were included, which is a limitation of this study. The results of the present study suggest that job-related stress mediates the effect of sleep reactivity on subjective cognitive dysfunction in Japanese adult workers. This underscores the need to evaluate the mediating effect of job-related stress in addressing the subjective cognitive dysfunction associated with insomnia in workers.
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http://dx.doi.org/10.2486/indhealth.2020-0251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426552PMC
September 2021

The Role of Cognitive Complaints in the Relationship Between Trait Anxiety, Depressive Symptoms, and Subjective Well-Being and Ill-Being in Adult Community Volunteers.

Neuropsychiatr Dis Treat 2021 30;17:1299-1309. Epub 2021 Apr 30.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.

Purpose: Trait anxiety, depressive symptoms, and cognitive complaints affect mental health. The mediating role of cognitive complaints has been reported recently. However, the mediating effects of cognitive complaints in the relationships between trait anxiety, depressive symptoms, and subjective well-being (SWB) and ill-being (SIB) remain unknown. Therefore, we used path analyses to investigate these mediating effects.

Materials And Methods: A total of 554 adult community volunteers in Japan were studied using the State-Trait Anxiety Inventory (Form Y), Patient Health Questionnaire-9, Cognitive Complaints in Bipolar Disorder Rating Assessment, and Subjective Well-Being Inventory. These assessment tools evaluated trait anxiety, depressive symptoms, cognitive complaints, SWB, and SIB. Path analyses were performed in this study.

Results: Path analyses revealed that there were significant indirect effects, via cognitive complaints, of trait anxiety and depressive symptoms on SIB. However, there were no significant indirect effects of trait anxiety and depressive symptoms on SWB. There were significant indirect effects, via depressive symptoms, of trait anxiety on cognitive complaints, SWB, and SIB.

Conclusion: The role of cognitive complaints may be different between SWB and SIB associated with trait anxiety and depressive symptoms. Evaluating the mediating effect of cognitive complaints may be more useful on SIB than SWB associated with trait anxiety and depressive symptoms. These findings may be useful when considering intervention targets in mental health.
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http://dx.doi.org/10.2147/NDT.S303751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096453PMC
April 2021

The Role of Cognitive Complaints in the Relationship Between Trait Anxiety, Depressive Symptoms, and Subjective Well-Being and Ill-Being in Adult Community Volunteers.

Neuropsychiatr Dis Treat 2021 30;17:1299-1309. Epub 2021 Apr 30.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.

Purpose: Trait anxiety, depressive symptoms, and cognitive complaints affect mental health. The mediating role of cognitive complaints has been reported recently. However, the mediating effects of cognitive complaints in the relationships between trait anxiety, depressive symptoms, and subjective well-being (SWB) and ill-being (SIB) remain unknown. Therefore, we used path analyses to investigate these mediating effects.

Materials And Methods: A total of 554 adult community volunteers in Japan were studied using the State-Trait Anxiety Inventory (Form Y), Patient Health Questionnaire-9, Cognitive Complaints in Bipolar Disorder Rating Assessment, and Subjective Well-Being Inventory. These assessment tools evaluated trait anxiety, depressive symptoms, cognitive complaints, SWB, and SIB. Path analyses were performed in this study.

Results: Path analyses revealed that there were significant indirect effects, via cognitive complaints, of trait anxiety and depressive symptoms on SIB. However, there were no significant indirect effects of trait anxiety and depressive symptoms on SWB. There were significant indirect effects, via depressive symptoms, of trait anxiety on cognitive complaints, SWB, and SIB.

Conclusion: The role of cognitive complaints may be different between SWB and SIB associated with trait anxiety and depressive symptoms. Evaluating the mediating effect of cognitive complaints may be more useful on SIB than SWB associated with trait anxiety and depressive symptoms. These findings may be useful when considering intervention targets in mental health.
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http://dx.doi.org/10.2147/NDT.S303751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096453PMC
April 2021

Mediating Roles of Cognitive Complaints on Relationships between Insomnia, State Anxiety, and Presenteeism in Japanese Adult Workers.

Int J Environ Res Public Health 2021 04 24;18(9). Epub 2021 Apr 24.

Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Sapporo 060-8638, Japan.

Complaints of cognitive functions (CCFs), defined as subjective cognitive dysfunction, affect social function; additionally, for workers, this condition is an important factor in presenteeism and mediates the effect of depressive symptoms on presenteeism. This study aimed to investigate whether CCFs mediate the relationships among insomnia, state anxiety (SA), and presenteeism. Participants were 471 Japanese adult workers evaluated using the Athens Insomnia Scale, State-Trait Anxiety Inventory (Form Y), Cognitive Complaints in Bipolar Disorder Rating Assessment, and Work Limitations Questionnaire 8 to assess insomnia, SA, CCFs, and presenteeism, respectively. Path analysis was used to evaluate the correlations between variables. CCFs significantly mediated the associations among insomnia, SA, and presenteeism. To address the presenteeism associated with insomnia and SA, it may be useful to assess the mediating roles of CCFs.
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http://dx.doi.org/10.3390/ijerph18094516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123047PMC
April 2021

Quantitative Resting State Electroencephalography in Patients with Schizophrenia Spectrum Disorders Treated with Strict Monotherapy Using Atypical Antipsychotics.

Clin Psychopharmacol Neurosci 2021 May;19(2):313-322

Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Objective: The effect of antipsychotic drugs on quantitative electroencephalography (EEG) has been mainly examined by the administration of a single test dose or among patients using combinations of other psychotropic drugs. We therefore investigated the effects of strict monotherapy with antipsychotic drugs on quantitative EEG among schizophrenia patients.

Methods: Data from 2,364 medical reports with EEG results from psychiatric patients admitted to the Hokkaido University Hospital were used. We extracted EEG records of patients who were diagnosed with schizophrenia spectrum disorders and who were either undergoing strict antipsychotic monotherapy or were completely free of psychotropic drugs. The spectral power was compared between drug-free patients and patients using antipsychotic drugs. We also performed multiple regression analysis to evaluate the relationship between spectral power and the chlorpromazine equivalent daily dose of antipsychotics in all the patients.

Results: We included 31 monotherapy and 20 drug-free patients. Compared with drug-free patients, patients receiving antipsychotic drugs demonstrated significant increases in theta, alpha and beta power. When patients taking different types of antipsychotics were compared with drug-free patients, we found no significant change in any spectrum power for the aripiprazole or blonanserin groups. Patients taking risperidone demonstrated significant increases in alpha and beta power. Patients taking clozapine and olanzapine demonstrated significant slow wave increases. Multiple regression analysis revealed that the chlorpromazine equivalent dose was positively associated with theta power.

Conclusion: Use of any antipsychotic drug by patients was associated with a dose-dependent increase in theta power. However, each type of antipsychotic demonstrated different spectral power changes.
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http://dx.doi.org/10.9758/cpn.2021.19.2.313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077067PMC
May 2021

Affective temperaments moderate the effect of insomnia on depressive symptoms in adult community volunteers.

J Affect Disord 2021 03 4;282:726-731. Epub 2021 Jan 4.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Sapporo 060-8638, Japan.

Background: Insomnia and affective temperaments influence depressive symptoms in the general population. However, the ways in which the interaction between insomnia and affective temperaments affects depressive symptoms remains unknown. We studied the moderating effects of affective temperaments on the relationship between insomnia and depressive symptoms in adult community volunteers.

Methods: The participants were recruited from a community in Japan (n = 525). The Athens Insomnia Scale; Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire version; and Patient Health Questionnaire-9 were used to evaluate insomnia, affective temperaments, and depressive symptoms, respectively. A hierarchical multiple regression analysis were conducted to evaluate the interactions.

Results: Insomnia significantly and positively interacted with cyclothymic, depressive, and anxious temperaments with regard to depressive symptoms, while insomnia significantly and negatively interacted with hyperthymic temperament on depressive symptoms. No significant interaction between insomnia and irritable temperament with regard to depressive symptoms were observed.

Limitations: Since the participants were adult community volunteers in Japan, the results may not be generalizable to other communities.

Conclusions: This study suggests that the influence of insomnia on depressive symptoms is moderated positively by cyclothymic, depressive, and anxious temperament and negatively by hyperthymic temperament. In adult community volunteers, affective temperaments may moderate the influence that insomnia has on depressive symptoms. Therefore, it may be useful to consider affective temperaments while dealing with depressive symptoms associated with insomnia.
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http://dx.doi.org/10.1016/j.jad.2020.12.138DOI Listing
March 2021

TEMPS-A (short version) plays a supplementary role in the differential diagnosis between major depressive disorder and bipolar disorder.

Psychiatry Clin Neurosci 2021 May 5;75(5):166-171. Epub 2021 Feb 5.

Department of Psychiatry, Tokyo Medical University, Tokyo, Japan.

Aim: Early differential diagnosis between patients with major depressive disorder (MDD) and bipolar disorder (BD), and subsequently providing appropriate treatments are essential. There has been increased interest regarding the association between affective temperaments and mood disorder diagnosis. Our aim was to analyze the diagnostic validity of affective temperaments assessed by the short version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A), in mood disorder patients.

Methods: Inpatients with MDD (n = 146) or BD (n = 128) completed the short version of TEMPS-A, and their depressive and manic symptom severities were evaluated. Data of MDD and BD patients were compared by univariable and multivariable analyses.

Results: Of the five affective temperament dimensions, substantially higher hyperthymic, irritable, and cyclothymic temperament scores were found in BD patients than in MDD patients. Using a multivariable logistic regression model built using the severities of depressed and manic conditions, and the five affective temperament subscale scores as independent variables, we identified two factors statistically associated with BD diagnosis (anxious temperament and cyclothymic temperament). The recommended cutoff point for the 12 items evaluating cyclothymic temperament to differentiate BD from MDD was 8 or more 'True' items (sensitivity: 35.9%, specificity: 87.7%).

Limitations: Our design was cross-sectional, and therefore, there was a possibility of longitudinal diagnostic conversion of patients from MDD to BD.

Conclusion: Cyclothymic and anxious temperaments on the short version of TEMPS-A, identified as diagnostic differentiating factors between MDD and BD, may play supplementary roles in the early identification of BD.
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http://dx.doi.org/10.1111/pcn.13198DOI Listing
May 2021

Prediction of lithium response using genomic data.

Sci Rep 2021 01 13;11(1):1155. Epub 2021 Jan 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
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http://dx.doi.org/10.1038/s41598-020-80814-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806976PMC
January 2021

Associations between cognitive impairment and illness awareness in fully remitted bipolar outpatients.

Psychiatry Res 2021 02 18;296:113655. Epub 2020 Dec 18.

Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

The euthymic state of bipolar disorder is often characterized by impaired cognitive function. In this investigation, we hypothesized that subjective cognitive function is impaired and illness awareness is inadequate and we further explored the associations among cognitive complaints, objective cognitive functions, and current illness awareness in Japanese patients. Twenty-seven patients in remission and 27 healthy subjects were recruited in this study. The Japanese version of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and Scale to Assess Unawareness in Mental Disorders (Japanese, SUMD-J) were used to assess each patient. All patients underwent neuropsychological tests for the assessment of objective cognitive functions. Only SUMD2.C (current awareness of the effects of medication) was significantly correlated with COBRA, and the objective cognitive assessments, Word Fluency Test and Stroop Test Reaction Time, represented significant correlations with SUMD1.C (current awareness of mental illness). In remitted bipolar outpatients, both the objective and subjective cognitive functions were found to be associated with illness awareness. However, subjective and objective cognitive functions differed in the related illness awareness subscales in fully remitted bipolar outpatients.
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http://dx.doi.org/10.1016/j.psychres.2020.113655DOI Listing
February 2021

A propensity score matching analysis for cardio metabolic risk of antipsychotics in patients with schizophrenia using Japanese claims data.

BMC Psychiatry 2020 12 9;20(1):584. Epub 2020 Dec 9.

Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, Japan.

Background: The aim of this study was to evaluate the cardio-metabolic risk in schizophrenia patients treated by atypical antipsychotic drugs compared with that in those treated without atypical antipsychotic drugs using a nationwide insurance claims database and medical examination database in Japan.

Methods: Eligible patients were defined as those meeting the following two criteria: (i) A diagnosis of schizophrenia (ICD-10 code: F20) was made between 1 January 2005 and 31 December 2017, with data available for at least 6 months before the diagnosis was made (index month), and (ii) health check-up data were available within ±3 months of the index month. The primary endpoint was changes in cardio-metabolic risk based on the Suita score at 1 year, and the secondary endpoints were changes in medical examination data related to cardio-metabolic risk (total cholesterol [TC], triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, body mass index [BMI], and hemoglobin A1c) at 1 year. The primary endpoint was evaluated by multivariate analysis, with the cumulative chlorpromazine equivalent amount and the baseline Suita score added as covariates.

Results: One-hundred eighty five pairs of propensity score (PS)-matched patients were evaluated. Patients receiving atypical antipsychotic drugs exhibited a greater change in the Suita score and a risk of coronary heart disease based on the Suita score of 0.530 and 0.098%, respectively, than patients not receiving atypical antipsychotic drugs, but there was no significant difference (p = 0.412 and 0.610). The significant changes in TC and BMI were determined as 6.525 mg/dL and 0.380 kg/m greater, respectively, in patients treated with atypical antipsychotic drugs (p = 0.037 and 0.011).

Conclusions: There were no significant increases in changes in the Suita score at 1 year by treatment with atypical antipsychotic drugs compared with treatment without atypical antipsychotic drugs. However, the TC and BMI were significantly higher in patients treated with atypical antipsychotic drugs.
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http://dx.doi.org/10.1186/s12888-020-02987-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724711PMC
December 2020

Personality traits mediate the association between perceived parental bonding and well-being in adult volunteers from the community.

Biopsychosoc Med 2020 19;14:28. Epub 2020 Oct 19.

Department of Psychiatry, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023 Japan.

Background: Previous studies reported that subjective well-being in adulthood correlates with perceived parental bonding in childhood as well as personality traits. However, whether personality traits mediate the effect of perceived parental bonding on well-being or not has not been reported to date. In this study, we hypothesized that 'parental care and overprotection' in childhood affect 'well-being' in adulthood through various 'personality traits', and analyzed this using structural equation modeling.

Methods: A total of 402 adult volunteers from the community provided responses to the following questionnaires: 1) Parental Bonding Instrument, 2) Temperament and Character Inventory, and 3) The Subjective Well-being Inventory. Two structural equation models were designed and the maximum likelihood estimation method was used for covariance structure analysis.

Results: Parental care in childhood directly increased well-being in adulthood and indirectly increased it through personality traits (harm avoidance, reward dependence, and self-directedness). Parental overprotection in childhood had no direct effect on well-being in adulthood but decreased well-being in adulthood indirectly through personality traits (harm avoidance, reward dependence, and self-directedness) and increased it through one personality trait (self-transcendence).

Conclusions: This study showed that the influences of perceived parental bonding on well-being in adulthood are mediated by self-directedness, harm avoidance, reward dependence, and self-transcendence among the seven personality dimensions evaluated by the Temperament and Character Inventory.
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http://dx.doi.org/10.1186/s13030-020-00198-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574412PMC
October 2020

Apathy in Alzheimer's Disease Correlates with the Dopamine Transporter Level in the Caudate Nuclei.

Dement Geriatr Cogn Dis Extra 2020 May-Aug;10(2):86-93. Epub 2020 Sep 9.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Introduction: Apathy is a common neuropsychiatric symptom in patients with Alzheimer's disease (AD). The striatal binding potential (BP) of I-FP-CIT (-δ-fluoropropyl-2β-carbomethoxy-3β-[4-iodophenyl]tropane) single-photon emission computed tomography (SPECT) is correlated with the degree of apathy in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). This study aimed to determine if dopaminergic activity in the basal ganglia is associated with the development of apathy in AD.

Methods: Nineteen subjects with AD were included and underwent I-FP-CIT-SPECT. Patients with other types of dementia as a comorbidity, those taking antidepressants, and those with overt parkinsonism were excluded. Apathy was assessed using the Apathy Evaluation Scale Informant-Japanese version (AES-I-J). SPECT images were overlaid with images in striatal regions of interest (ROIs), and the SPECT values in these regions were counted. The relationship between BP values and AES-I-J scores was investigated using Spearman's rank correlation coefficient.

Results: Significant inverse correlations were observed between BP values and AES-I-J scores in the left caudate nucleus and there was a marginally significant inverse correlation in the right caudate nucleus.

Conclusion: The pathological basis of apathy might be the impairment of the dopaminergic nervous system. Further studies on more subjects with AD, healthy controls, and patients with PD and DLB are needed.
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http://dx.doi.org/10.1159/000509278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548940PMC
September 2020

Structural equation modeling approach to explore the influence of childhood maltreatment in adults.

PLoS One 2020 1;15(10):e0239820. Epub 2020 Oct 1.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita, Nishi, Sapporo, Japan.

Background: Childhood maltreatment affects social functioning in the general adult population. However, how child abuse affects functional disability in adulthood remains unknown. Thus, we investigated the correlation between child abuse, depressive symptoms, cognitive complaints, and functional disability in adult community volunteers.

Methods: Participants (N = 556) completed the Child Abuse and Trauma Scale, Patient Health Questionnaire-9, Cognitive Complaints in Bipolar Disorder Rating Assessment, and Sheehan Disability Scale. Multiple regression analyses and structural equation modeling were performed to evaluate scale correlations.

Results: Structural equation modeling showed that the direct effect of childhood maltreatment on depressive symptoms, the indirect effect of childhood maltreatment on cognitive function via depressive symptoms, and the indirect effects of childhood maltreatment on functional disability via depressive symptoms and via cognitive function were all significant. The direct effects of childhood maltreatment on cognitive function and functional disability were not significant. There was no significant association between variables.

Limitations: Cross-sectional designs cannot identify causal relationships between parameters. Participants were adult volunteers from the community; therefore, results may not be generalizable to individuals with psychiatric disorders. Sociodemographic variability was a limitation because we used self-reported childhood maltreatment.

Conclusions: Childhood maltreatment indirectly affects functional disability via depressive symptoms and via cognitive function through depressive symptoms. We suggest that depressive symptoms and cognitive function play crucial roles in the influence of childhood maltreatment on functional disability in adult community volunteers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529428PMC
November 2020

Impact of a Rice-Centered Diet on the Quality of Sleep in Association with Reduced Oxidative Stress: A Randomized, Open, Parallel-Group Clinical Trial.

Nutrients 2020 Sep 24;12(10). Epub 2020 Sep 24.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan.

Previously, we found that a Japanese diet was associated with psychological status, and a combination of rice and miso was related to mental and physical health. We hypothesized that the intake of a rice-based diet affected mental and physical health and aimed to investigate the consequences of a dietary intervention with rice. We conducted a randomized, open-label, parallel-group clinical trial that included 60 participants, who were randomly assigned to receive either rice-based meals or meals with other cereals for three daily meals over 2 months. The participants were surveyed for psychological status and biochemical changes. Sleep quality index scores showed significant improvement after the rice-based intervention. Additionally, blood oxidative stress levels were reduced in the rice-diet group compared with the no-rice-diet group. Although the molecular mechanisms should be investigated in detail, our findings suggest that controlling oxidative stress through the intake of a rice-centered diet may be key to improving sleep quality.
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http://dx.doi.org/10.3390/nu12102926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650672PMC
September 2020

Associations among childhood parenting, affective temperaments, depressive symptoms, and cognitive complaints in adult community volunteers.

J Affect Disord 2020 11 21;276:361-368. Epub 2020 Jul 21.

Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Background: Correlations between depressive symptoms and affective temperaments or quality of childhood parenting have been investigated previously; however, how childhood parenting and affective temperaments affect cognitive complaints remains unknown. Thus, we evaluated correlations among childhood parenting, affective temperaments, depressive symptoms, and cognitive complaints in adults.

Methods: Participants (N = 490) completed the Parental Bonding Instrument (PBI), Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire version (TEMPS-A), the Patient Health Questionnaire-9 (PHQ-9), and the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA). Multiple regression analyses and structural equation modeling were performed to evaluate scale correlations.

Results: As per structural equation modeling, the direct effect of PHQ-9 and four subscales (cyclothymic, depressive, irritable, and anxious temperament) of TEMPS-A on COBRA were significant; the indirect effect of the four subscales of TEMPS-A on COBRA via PHQ-9 was significant; the direct effect of the three subscales (paternal care, maternal care, and maternal overprotection) of PBI on PHQ-9 and four subscales of TEMPS-A were significant; the indirect effect of the three subscales of PBI on PHQ-9 via the four subscales of TEMPS-A was significant.

Limitations: Cross-sectional designs cannot identify causal relationships between parameters. As participants were adult volunteers from the community, results may not be generalizable to individuals with psychiatric disorders.

Conclusions: Childhood parenting affects cognitive complaints indirectly via affective temperaments and depressive symptoms in adult community volunteers. An important role of affective temperaments and depressive symptoms in the effects of childhood parenting on cognitive complaints is suggested.
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http://dx.doi.org/10.1016/j.jad.2020.07.107DOI Listing
November 2020

Association Between -Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by -Desmethylclozapine.

J Pharmacol Exp Ther 2020 11 29;375(2):376-384. Epub 2020 Aug 29.

Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.).

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and Drooling Severity and Frequency Scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells) and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva -desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, -desmethylclozapine concentrations in serum and submandibular glands of the rats were higher than clozapine concentrations. In our in vitro study, -desmethylclozapine only elicited an increase in the intracellular Ca in HSY cells. -desmethylclozapine-induced Ca responses were inhibited by atropine. These results suggest that -desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research. SIGNIFICANCE STATEMENT: Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction, but the mechanism underlying CIS is less well understood. This paper reports that -desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.
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http://dx.doi.org/10.1124/jpet.120.000164DOI Listing
November 2020

Does Subjective Cognitive Function Mediate the Effect of Affective Temperaments on Functional Disability in Japanese Adults?

Neuropsychiatr Dis Treat 2020 8;16:1675-1684. Epub 2020 Jul 8.

Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Purpose: Functional disability is affected by subjective cognitive function, depressive symptoms, and affective temperaments in adults. However, the role of subjective cognitive function as a mediator of affective temperaments in functional disability remains unknown. Therefore, we aimed to determine how subjective cognitive function mediates the effect of affective temperaments on functional disability in adults.

Materials And Methods: A total of 544 participants completed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Auto questionnaire version (TEMPS-A), the Patient Health Questionnaire-9 (PHQ-9), the cognitive complaints in bipolar disorder rating assessment (COBRA), and the Sheehan Disability Scale (SDS). The association among these instruments was evaluated by multiple regression and covariance structure analyses.

Results: The structural equation model showed that the COBRA scores could be predicted directly by the four affective temperaments of the TEMPS-A (cyclothymic, depressive, irritable, and anxious) and indirectly by the PHQ-9. Moreover, the SDS score was predicted directly by these four affective temperaments and indirectly by the COBRA and PHQ-9.

Conclusion: Subjective cognitive function mediates the effect of affective temperaments on functional disability in Japanese adults. However, the cross-sectional design may limit the identification of causal associations between the parameters. In the present study, the participants were from a specific community population; therefore, the results may not be generalizable to other communities.
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http://dx.doi.org/10.2147/NDT.S256647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354955PMC
July 2020

Associations between cognitive impairment and P300 mean amplitudes in individuals with bipolar disorder in remission.

Psychiatry Res 2020 08 29;290:113125. Epub 2020 May 29.

Department of Psychiatry, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Cognitive functions are often affected during the euthymic state of bipolar disorder (BD). In this study, we investigated the associations among cognitive complaints, objective cognitive functions, and the mean amplitudes of the P300 event-related potential (ERP) wave in individuals with BD. The study population comprised 33 individuals with BD who were in remission and was conducted at Hokkaido University Hospital, Sapporo, Japan. Cognitive complaints were assessed using the Japanese version of the tool named "cognitive complaints in bipolar disorder rating assessment (COBRA)", whereas objective cognitive functions were measured by neuropsychological tests. P300 mean amplitudes were investigated during two- and three-stimulus oddball tasks and showed significant correlations with neuropsychological test scores at all electrode locations, confirming that ERPs and objective cognitive tests that assessed attention and memory function tend to coincide; however, neither P300 amplitudes nor neuropsychological test scores were correlated with COBRA scores. ERPs most likely represent the neurophysiological basis for objective rather than subjective cognitive function in euthymic individuals. Thus, our results suggest that objective cognitive function is related more to P300 mean amplitude scores than subjective cognitive function in individuals with BD.
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http://dx.doi.org/10.1016/j.psychres.2020.113125DOI Listing
August 2020

Changes in subunit composition of NMDA receptors in animal models of schizophrenia by repeated administration of methamphetamine.

Prog Neuropsychopharmacol Biol Psychiatry 2020 12 28;103:109984. Epub 2020 May 28.

Department of Psychiatry, Hokkaido University Graduate School of Medicine, West 7, North 15, Kita Ward, Sapporo City, Hokkaido 060-8638, JAPAN. Electronic address:

The dopamine and glutamate hypotheses reflect only some of the pathophysiological changes associated with schizophrenia. We have proposed a new "comprehensive progressive pathophysiology model" based on the "dopamine to glutamate hypothesis." Repeated administration of methamphetamine (METH) at a dose of 2.5 mg/kg in rats has been used to assess dynamic changes in the pathophysiology of schizophrenia. Previous use of this model suggested N-methyl-d-aspartate receptor (NMDA-R) dysfunction, but the mechanism could only be inferred from limited, indirect observations. In the present study, we used this model to investigate changes in the expression of NMDA-R subunits. Repeated administration of METH significantly decreased the gene expression levels of glutamate ionotropic receptor NMDA type subunit (Grin) subtypes Grin1 and Grin2c in the prefrontal cortex (PFC), Grin1 and Grin2a in the hippocampus (HPC), and Grin1, Grin2b, and Grin2d in the striatum (ST).We observed a significant difference in Grin1 expression between the PFC and ST. Furthermore, repeated administration of METH significantly decreased the protein expression of GluN1 in both cytosolic and synaptosomal fractions isolated from the PFC, and significantly decreased the protein expression of GluN1 in the cytosolic fraction, but not the synaptosomal fraction from the ST. These regional differences may be due to variations in the synthesis of GluN1 or intracellular trafficking events in each area of the brain. Considering that knockdown of Grin1 in mice affects vulnerability to develop schizophrenia, these results suggest that this model reflects some of the pathophysiological changes of schizophrenia, combining both the dopamine and glutamate hypotheses.
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http://dx.doi.org/10.1016/j.pnpbp.2020.109984DOI Listing
December 2020

Utility of TEMPS-A in differentiation between major depressive disorder, bipolar I disorder, and bipolar II disorder.

PLoS One 2020 22;15(5):e0232459. Epub 2020 May 22.

Department of Psychiatry, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.

Background: The association between temperament characteristics and mood disorders has gained much attention in recent years. The Temperament Evaluation of Memphis, Pisa, Paris and San Diego-autoquestionnaire version (TEMPS-A) is a self-rating scale measuring 5 affective temperament dimensions. In this study, we aimed to clarify whether each affective temperament of TEMPS-A is a differentiating factor between major depressive disorder (MDD), bipolar I disorder (BD-I), and bipolar II disorder (BD-II), and analyzed the utility of TEMPS-A in their differential diagnosis in a clinical setting.

Methods: A total of 346 patients (MDD, n = 176; BD-II, n = 112; BD-I, n = 58) filled out TEMPS-A. To assess the patients' mood state at the time of temperament assessment, Patient Health Questionnaire-9 (PHQ-9) and Young Mania Rating Scale (YMRS) were also conducted.

Results: Multivariate logistic regression analysis demonstrated that cyclothymic and anxious temperament scores were significant factors differentiating the diagnosis of BD-I and BD-II from the diagnosis of MDD, and hyperthymic temperament score was a specific factor for the differential diagnosis of BD-I versus the diagnosis of BD-II.

Limitations: All of the patients included in our study received treatment in large general hospitals. Because the nature of the present study was cross-sectional, some MDD subjects in this study might have unrecognized BD-I/BD-II.

Conclusions: Cyclothymic and anxious temperament scores assessed by TEMPS-A might enable differentiation between MDD and BD, and hyperthymic temperament score on TEMPS-A might be useful in distinguishing between BD-I and BD-II.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232459PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244116PMC
July 2020
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