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BackgroundsHikikomori, pathological social withdrawal, is becoming a crucial mental health issue in Japan and worldwide. We have developed a 3-day family intervention program for hikikomori sufferers based on Mental Health First Aid (MHFA) and Community Reinforcement and Family Training (CRAFT). This study aims to confirm the effectiveness of the 3-day program by a randomized controlled trial.MethodsThis study was registered on the UMIN Clinical Trials Registry (UMIN000037289). Fifteen parents were assigned to the treat as usual (TAU) group (TAU only; Age Mean, 65.6; SD, 7.8), and 14 to the Program group (program + TAU; Age Mean, 67.9; SD, 8.6). This study was discontinued due to the COVID-19 pandemic; the recruitment rate was 36.3% of our target sample size of 80.ResultsPerceived skills improved temporally and stigma temporally worsened in the TAU group. Confidence decreased and attitude showed no change in both groups. Aggressive behaviors of hikikomori sufferers were significantly worsened in the Program group; however, no serious domestic violence was reported. In the TAU group, Avoidance and irregular life patterns were improved. Activity levels were worsened in both groups. Two participants (16.7%) in the Program group and one participant (7.7%) in the TAU group reported actual behavioral changes (e.g., utilizing support).ConclusionWe could not draw general conclusions on the effectiveness of the program due to the study discontinuation. Nevertheless, this study indicates the necessity for revision of the program to improve family members’ confidence in engaging with hikikomori sufferers, with safer approaching by families.

Abstract Interpersonal difficulties are often observed in major depressive disorder (MDD), while the underlying psychological and biological mechanisms have not yet been elucidated. In the present case–control study, a PC-based trust game was conducted for 38 drug-free MDD patients and 38 healthy controls (HC). In the trust game, participants invested money in a partner (trusting behaviors), and also rated each partner’s attractiveness (preference for others). In addition, blood biomarkers including metabolites were measured. Both MDD and HC males exhibited more trusting behaviors compared to females. MDD males’ preference for ordinary-attractive partners (lay-person photographs) was lower than HC males, whereas their preference for high-attractive females (fashion-model photographs) was similar levels to HC males. This tendency in MDD males could reflect a “focused (narrowed) preference for females”. As for blood biomarker analysis, the levels of 37 metabolites including acetylcholine, AMP, GMP, nicotinic acid and tryptophan were significantly different between two groups. Interestingly, among male participants, acetylcholine and nicotinic acid were negatively correlated with the level of focused preference for photographed females. In sum, we have revealed some behavioral, psychological and biological traits of trusting behaviors and preference for others especially in MDD males. Larger studies should be conducted to validate our preliminary findings.

Abstract Aim Neurofibromatosis type 1 (NF1) is a multifaceted disease, and frequently comorbid with neurodevelopmental disorders such as autism spectrum disorder (ASD) and learning disorder. Dysfunction of adenylyl cyclase (AC) is one of the candidate pathways in abnormal development of neuronal cells in the brain of NF1 patients, while its dynamic abnormalities have not been observed. Direct conversion technology can generate induced‐neuronal (iN) cells directly from human fibroblasts within 2 weeks. Just recently, we have revealed that forskolin, an AC activator, rescues the gene expression pattern of iN cells derived from NF1 patients (NF1‐iN cells). In this microreport, we show the dynamic effect of forskolin on NF1‐iN cells. Methods iN cells derived from healthy control (HC‐iN cells) and NF1‐iN cells were treated with forskolin (final concentration 10 μM), respectively. Morphological changes of iN cells were captured by inverted microscope with CCD camera every 2 minutes for 90 minutes. Results Prior to forskolin treatment, neuron‐like spherical‐form cells were observed in HC‐iN cells, but most NF1‐iN cells were not spherical‐form but flatform. Only 20 minutes after forskolin treatment, the morphology of the iN cells were dramatically changed from flatform to spherical form, especially in NF1‐iN cells. Conclusion The present pilot data indicate that forskolin or AC activators may have therapeutic effects on the growth of neuronal cells in NF1 patients. Further translational research should be conducted to validate our pilot findings for future drug development of ASD.

Abstract Background The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. Methods The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. Results The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer’s disease. Conclusions The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.

Background: The association between decline in handgrip strength from midlife to late life and dementia is unclear. Methods: Japanese community-dwellers without dementia aged 60 to 79 years (ie, individuals in late life; mean age, 68 years) were followed for 24 years (1988–2012) (n = 1,055); 835 of them had participated in a health examination in 1973–1974 (mean age, 53 years), and these earlier data were used for the midlife analysis. Using a Cox proportional hazards model, we estimated the risk conferred by a decline in handgrip strength over a 15-year period (1973–74 to 1988) from midlife to late life on the development of total dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) over the late-life follow-up period from 1988 to 2012. Results: During the follow-up, 368 subjects experienced total dementia. The age- and sex-adjusted incidence of total dementia increased significantly with greater decline in handgrip strength (increased or unchanged handgrip strength [≥+0%] 25.1, mildly decreased [−14 to −1%] 28.4, and severely decreased [≤−15%] 38.9 per 1,000 person-years). A greater decline in handgrip strength was significantly associated with higher risk of total dementia after adjusting for potential confounding factors; subjects with severely decreased handgrip strength had 1.51-fold (95% confidence interval, 1.14–1.99, P < 0.01) increased risk of total dementia compared to those with increased or unchanged handgrip strength. Similar significant findings were observed for AD, but not for VaD. Conclusions: Our findings suggest that a greater decline in handgrip strength from midlife to late life is an important indicator for late-life onset of dementia.

Abstract Background In an 8-week, randomized, placebo-controlled, double-blind study, an extended-release formulation of quetiapine, quetiapine XR, demonstrated efficacy and safety in Japanese patients with bipolar depression. Bipolar disorder is a chronic disease requiring continuous treatment. Methods This was a long-term (52-week), open-label, non-controlled extension study to evaluate the long-term safety and efficacy of quetiapine XR in Japanese patients with bipolar depression who had previously completed the initial 8-week double-blind study. Efficacy was determined by the Montgomery–Åsberg Depression Rating Scale (MADRS), Hamilton Depression Scale 17-item (HAM-D17), and Clinical Global Impressions-Bipolar scale (CGI-BP). Safety evaluations included analysis of adverse events, clinical laboratory measures, vital signs, Drug-induced Extrapyramidal Symptoms Scale, Young Mania Rating Scale, and the Columbia Suicide Severity Rating Scale. Results The mean (SD) MADRS total score decreased from 30.9 (6.9) at baseline to 16.1 (10.6) at week 8, and eventually to 9.1 (8.7) at week 52. The sustained efficacy of quetiapine XR treatment was also shown using HAM-D17 total scores, CGI-BP-Severity and Change evaluations. The most common adverse events were somnolence, nasopharyngitis, and thirst. Long-term treatment with quetiapine XR caused no substantial changes in the safety profiles, including clinical laboratory parameters, and no new safety concerns were identified. Conclusions The efficacy of quetiapine XR was sustained long-term and no new safety concerns were identified in Japanese patients with bipolar depression. Trial registration ClinicalTrials.gov Registration: NCT01725308. Date of registration; 12th November 2012 (retrospectively registered).

Background: Although disorganized speech is seen as one of the nuclear features of schizophrenia, there have been few reports of disorganized speech-associated psychotropic drug-prescribing patterns in large samples of schizophrenia patients. Objective: We aimed to examine the prevalence of disorganized speech and its correlates in terms of psychotropic drug prescribing, using the data from the Research on Asian Psychotropic Patterns for Antipsychotics (REAP-AP) study. Method: A total of 3744 patients with the ICD-10 diagnosis of schizophrenia were enrolled from 71 survey centers in 15 Asian countries/areas. An essential criterion of disorganized speech was that it was “severe enough to impair substantially effective communication” as defined in the DSM-5. A binary logistic model was fitted to identify the psychotropic drug-prescribing correlates of disorganized speech. Results: After adjusting for the potential effects of confounding variables, the binary logistic regression model showed that the presence of disorganized speech was directly associated with adjunctive use of mood stabilizers (P

Not a few patients with obsessive-compulsive disorder (OCD) have experienced events that affected the onset. The onset of OCD is not limited to the original meaning of trauma; rather, traumatic experiences such as unexpected exposure to contaminants or various stressful life events often cause the onset of OCD. It would be useful to understand the experiences surrounding the onset, including stressful life events and traumatic experiences, for comprehension of the pathophysiology of OCD. In the present study, we investigated the onset conditions of 281 patients with OCD and compared clinical characteristics among groups with or without stressful life events including traumatic experiences. As a result, 172 (61.2%) participants had experienced various stressful life events, and 98 (34%) participants had had traumatic experiences before the onset. Furthermore, the participants who had had stressful life events showed more contamination/fear symptoms compared with those without such life events. Meanwhile, the patients who had had specific traumatic experiences showed a tendency toward hoarding obsessions. To comprehend the pathophysiology of OCD, it is important to understand the stressful life events that precede its onset.

Previous studies have reported clinical characteristics of hoarding disorder (HD), such as early onset, a chronic course, familiality, high unmarried rate, and high rates of comorbidities. However, clinical research targeting Japanese HD patients has been very limited. As a result, there is a low recognition of HD in Japan, leading to insufficient evaluation and treatment of Japanese HD patients.The aim of the current study was to delineate the clinical characteristics of Japanese HD patients. Thirty HD patients, 20 obsessive-compulsive disorder (OCD) patients, and 21 normal controls (NC) were targeted in this study.The HD group had a tendency toward higher familiality, earlier onset, and longer disease duration compared to the OCD group. In addition, the HD group showed a significantly higher unmarried rate than the NC group. The top two comorbidities in the HD group were major depressive disorder (56.7%) and attention-deficit/hyperactivity disorder (26.7%). The HD group had significantly higher scores on hoarding rating scales and lower scores on the Global Assessment of Functioning Scale than the other two groups.The current study showed a clinical trend in Japanese HD patients similar to previous studies in various countries, suggesting that HD may be a universal disease with consistent clinical symptoms.

Backgrounds: Hikikomori, a severe form of social withdrawal, is increasingly a serious mental health issue worldwide. Hikikomori is comorbid with various psychiatric conditions including depression, social anxiety and suicidal behaviors. Family support is encouraged as a vital first step, however evidence-based programs have yet to be established. Mental Health First Aid (MHFA) is one of the most well-validated educational programs encouraging lay people such as family members, to support close persons suffering from various psychiatric conditions such as depression, anxiety and suicidal behaviors. Methods: We newly developed an educational program for family members of hikikomori sufferers mainly based on MHFA and ‘Community Reinforcement and Family Training (CRAFT)’ with role-play and homework. As a single-arm trial, 21 parents (7 fathers and 14 mothers) living with hikikomori sufferers participated in our program with five once-a-week sessions (2 h per session) and six monthly follow-ups, and its effectiveness was evaluated using various self-rated questionnaires. Results: Perceived skills toward a depressed hikikomori case vignette, stigma held by participants, and subscales of two problematic and one adaptive behaviors of hikikomori sufferers were improved throughout the sessions and follow-ups. In addition, positive behavioral changes of hikikomori sufferers such as improved social participation were reported by participants. Limitations: Single-arm design and evaluation using self-rated questionnaires are the main limitations of the present study. Conclusions: Our newly developed program has positive effects on family members in their contact and support of hikikomori sufferers. Future trials with control groups are required to validate the effectiveness of this program.

Our study aimed to assess the psychometric validity of the conceptual disorganization item and other items of the Brief Psychiatric Rating Scale (BPRS) for detecting disorganized speech in patients with schizophrenia. We included 357 schizophrenia patients with disorganized speech and 1082 without disorganized speech from the survey centers in India, Indonesia, Japan, Malaysia, and Taiwan, using the data from the Research on Asian Psychotropic Patterns for Antipsychotics (REAP-AP) study. After adjusting the effects of confounding variables, a binary logistic regression model was fitted to identify BPRS items independently associated with disorganized speech. Receiver operating characteristic (ROC) curves were used to identify optimum cut-off scores and their sensitivities and specificities for detecting disorganized speech. After adjusting the effects of confounding variables, the fitted binary logistic regression model indicated that conceptual disorganization (P

Abstract Social isolation is an important factor in the development of psychiatric disorders. It is necessary to develop an effective psychological treatment, such as cognitive rehabilitation, for children who have already suffered from social isolation, such as neglect and social rejection. We used socially isolated mice to validate whether elaborate re-socialization after juvenile social isolation can restore hypomyelination in the medial prefrontal cortex (mPFC) and the attendant functions manifested in socially isolated mice. While mice who underwent re-socialization with socially isolated mice after juvenile social isolation (Re-IS mice) demonstrated less mPFC activity during exposure to a strange mouse, as well as thinner myelin in the mPFC than controls, mice who underwent re-socialization with socially housed mice after juvenile social isolation (Re-SH mice) caught up with the controls in terms of most mPFC functions, as well as myelination. Moreover, social interaction of Re-IS mice was reduced as compared to controls, but Re-SH mice showed an amount of social interaction comparable to that of controls. These results suggest that the mode of re-socialization after juvenile social isolation has significant effects on myelination in the mPFC and the attendant functions in mice, indicating the importance of appropriate psychosocial intervention after social isolation.

Background Epidemiological evidence implies a link between heart disease and dementia. However, few prospective studies have assessed the association between serum NT‐proBNP (N‐terminal pro–B‐type natriuretic peptide) levels and dementia. Methods and Results A total of 1635 community‐dwelling Japanese elderly aged ≥60 years without dementia (57% women, mean age±SD 70.8±7.7 years) were followed up for 10 years. Serum NT‐proBNP levels were divided into 4 categories (≤54, 55‐124, 125‐299, and ≥300 pg/mL). The hazard ratios were estimated using a Cox proportional hazards model. During the follow‐up period, 377 subjects developed all‐cause dementia, 247 Alzheimer disease, and 102 vascular dementia. The age‐ and sex‐adjusted incidence of all‐cause dementia was 31.5 per 1000 person‐years and increased significantly with higher serum NT‐proBNP levels, being 16.4, 32.0, 35.7, and 45.5, respectively (P for trend

Hikikomori, a form of severe social withdrawal more than 6 months, has increasingly become a crucial issue especially among adolescents. Loneliness, avoidant personality, Japanese culture-related attachment style (“amae”), and difficulty in expressing emotions are suggested to be related to hikikomori. However, deeper psychological aspects have not been well clarified. The Rorschach test is one of the most popular psychological assessment tools to evaluate deeper personality traits. The Rorschach Comprehensive System (CS) has been established as the most reliable scoring method. Until now, no CS research has been conducted focusing on hikikomori. Therefore, we herein conducted a pilot case–control study using CS in clinical cases with and without hikikomori condition. Participants were recruited from the Mood Disorder/Hikikomori Clinic at Kyushu University Hospital. Twenty-two patients with hikikomori (HK patients) and 18 patients without hikikomori (non-HK patients) participated in the present study. All the 40 participants conducted the self-report Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) personality questionnaire and CS. Regarding the SCID-II personality questionnaire, various personality traits including passive aggressive trait were significantly higher in HK patients. Among CS variables, HK patients showed higher scores on FC (Form Color) and SumT (total number of texture-related responses). In addition, frequency of SumT was higher in HK patients. The present results suggest that persons with hikikomori are more likely to express emotions indirectly and expect others to presume their feelings and thoughts. Persons with hikikomori may also have difficulty in becoming independent emotionally from primitive dependence and attachment on significant others. Further investigations with larger samples are warranted for validation.

Suicide is one of the most disastrous outcomes for psychiatric disorders. Recent advances in biological psychiatry have suggested a positive relationship between some specific brain abnormalities and specific symptoms in psychiatric disorders whose organic bases were previously completely unknown. Microglia, immune cells in the brain, are regarded to play crucial roles in brain inflammation by releasing inflammatory mediators and are suggested to contribute to various psychiatric disorders such as depression and schizophrenia. Recently, activated microglia have been suggested to be one of the possible contributing cells to suicide and suicidal behaviors via various mechanisms especially including the tryptophan-kynurenine pathway. Animal model research focusing on psychiatric disorders has a long history, however, there are only limited animal models that can properly express psychiatric symptoms. In particular, to our knowledge, animal models of human suicidal behaviors have not been established. Suicide is believed to be limited to humans, therefore human subjects should be the targets of research despite various ethical and technical limitations. From this perspective, we introduce human biological studies focusing on suicide and microglia. We first present neuropathological studies using the human postmortem brain of suicide victims. Second, we show recent findings based on positron emission tomography (PET) imaging and peripheral blood biomarker analysis on living subjects with suicidal ideation and/or suicide-related behaviors especially focusing on the tryptophan-kynurenine pathway. Finally, we propose future perspectives and tasks to clarify the role of microglia in suicide using multi-dimensional analytical methods focusing on human subjects with suicidal ideation, suicide-related behaviors and suicide victims.

Background: Impaired cognitive flexibility has been implicated in the genetic basis of obsessive-compulsive disorder (OCD). Recent endophenotype studies of OCD showed neural inefficiency in the cognitive control network and interference by the limbic network of the cognitive control network. Exploring the relationship between the functional brain network and impaired cognitive flexibility may provide novel information about the neurobiological basis of OCD. Methods: We obtained resting-state functional magnetic resonance imaging (rsfMRI) scans and measured the cognitive flexibility of 37 medication-free OCD patients and 40 healthy control (HC) participants using the Wisconsin Card Sorting Test (WCST). We explored the difference between OCD and HC groups in the functional brain network related to impaired cognitive flexibility from the amygdala and dorsal striatal regions of interest (ROIs) by using a seed-based approach. Results: Significant differences between the OCD and HC groups were identified in the resting state functional network from the dorsal caudate. Increased functional connectivity from the dorsal caudate to the dorsal anterior cingulate cortex (dACC) and anterior insula (AI) was associated with poorer cognitive flexibility in the OCD group, but better cognitive flexibility in the HC group. Conclusions: These results provide evidence that the impaired cognitive flexibility of OCD may be associated with dysfunctions of the brain network from the dorsal caudate (DC) to important nodes of the salience network. Our results extend the neuropsychological model of OCD by showing intrinsically different associations between OCD and HC in functional network and cognitive flexibility. Keywords: Obsessive-compulsive disorder, Cognitive flexibility, Salience network, Dorsal caudate, Functional connectivity, Resting state functional MRI

Recent MRI studies have shown that schizophrenia is characterized by reductions in brain gray matter, which progress in the acute state of the disease. Cortical circuitry abnormalities in gamma oscillations, such as deficits in the auditory steady state response (ASSR) to gamma frequency (>30-Hz) stimulation, have also been reported in schizophrenia patients. In the current study, we investigated neural responses during click stimulation by BOLD signals. We acquired BOLD responses elicited by click trains of 20, 30, 40 and 80-Hz frequencies from 15 patients with acute episode schizophrenia (AESZ), 14 symptom-severity-matched patients with non-acute episode schizophrenia (NASZ), and 24 healthy controls (HC), assessed via a standard general linear-model-based analysis. The AESZ group showed significantly increased ASSR-BOLD signals to 80-Hz stimuli in the left auditory cortex compared with the HC and NASZ groups. In addition, enhanced 80-Hz ASSR-BOLD signals were associated with more severe auditory hallucination experiences in AESZ participants. The present results indicate that neural over activation occurs during 80-Hz auditory stimulation of the left auditory cortex in individuals with acute state schizophrenia. Given the possible association between abnormal gamma activity and increased glutamate levels, our data may reflect glutamate toxicity in the auditory cortex in the acute state of schizophrenia, which might lead to progressive changes in the left transverse temporal gyrus.

ObjectiveIn the workplace depression and suicide are serious mental health problems. A lack of knowledge and mental health skills along with the stigma toward mental health problems often results in delays in seeking professional help. Interventions targeting not only persons with mental health problems but also people around the individual are warranted in order to encourage supporting behavior within entire workplace. In the present study, we investigated the efficacy of our newly developed educational training program in the management with depression and suicidal risk in the workplace as a single-arm pilot trial.MethodsThe program is a two-hour (2-h) training course for employees based on the Mental Health First Aid (MHFA) program which aims to increase public mental health literacy. We conducted this program at a company workplace among 91 employees, and ultimately 83 participants completed the self-rated questionnaires. Changes in confidence and practical skills in early intervention of depression and suicide-prevention, and stigma toward mental health problems were evaluated using self-rated questionnaires at 3 time-points; pre-program, immediately post-program, and 1 month after the program.ResultsConfidence and practical skills were significantly improved even 1 month after the program, and stigma reduced just after the program.ConclusionsOur pilot study suggests that the program has a positive impact on encouraging employees to support their co-workers with mental health problems, and is applicable for busy workers due to its short duration. A single-arm design, evaluation using self-rated questionnaire and short-term follow up period are the main limitations of the present study. Hence, future research is required to validate the effects of this program with control groups, and also to assess long-term effectiveness and objective changes such as absenteeism and sick leave.Trial registrationUMIN Clinical Trials Registry (UMIN-CTR) R000023258.

BACKGROUND:Hoarding disorder (HD) is a disease concept newly presented in DSM-5. As far as we know, no studies have examined the structural changes relevant to hoarding by applying the diagnostic criteria of HD in DSM-5. In the present study, we aimed to find abnormalities in gray matter (GM) structures of patients with HD. METHODS:Seventeen patients who met the DSM-5 criteria for HD, 17 obsessive-compulsive disorder (OCD) patients, and 17 healthy controls (HCs) participated in this study. All participants underwent MRI scanning of the brain by a 3.0-Tesla MRI scanner. In a voxel-based morphometric procedure, preprocessed GM structural images were used to compare the three groups. Thereafter we investigated the correlation between the clinical data (age of onset, symptomatic severity) and GM volume. RESULTS:The HD group showed a significantly increased GM volume compared to the OCD and healthy control groups (p

The tail suspension test (TST) has been widely used as a screening assay for antidepressant drugs. However, the neural substrates underlying the stress response and antidepressant-like effect during the TST remain largely unknown despite the prevalence of this test. In the present study, we used immunohistochemistry to examine alterations in c-Fos expression as a measure of neuronal activity in the mouse brain after acute administration of the antidepressant drugs nortriptyline or escitalopram (or saline as a control) with or without a subsequent TST session. We found that without the TST session, nortriptyline administration enhanced the density of c-Fos-immunoreactive cells in regions of the central extended amygdala, paraventricular hypothalamic nucleus, and relevant regions of the brain stem, whereas escitalopram did not change c-Fos expression in any region. Following the TST in the absence of antidepressant drugs, we observed a significant increase in c-Fos-positive cell density in a number of brain regions within the limbic telencephalon, hypothalamus, and brain stem. We detected a statistically significant interaction using an analysis of variance between the main effects of the drug and stress response in four regions: the infralimbic cortex, lateral septal nucleus (intermediate part), ventrolateral preoptic nucleus, and solitary nucleus. Following the TST, escitalopram but not nortriptyline increased c-Fos-positive cell density in the infralimbic cortex and ventrolateral preoptic nucleus, whereas nortriptyline but not escitalopram increased c-Fos expression in the solitary nucleus. Both antidepressants significantly increased c-Fos expression in the lateral septal nucleus (intermediate part). The present results indicate that neuronal activity increases in septo-hypothalamic regions and related structures, especially the lateral septal nucleus, following administration of drugs producing an antidepressant-like effect in mice subjected to the TST.

New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.

Evaluating the severity of depression (SOD), especially suicidal ideation (SI), is crucial in the treatment of not only patients with mood disorders but also psychiatric patients in general. SOD has been assessed on interviews such as the Hamilton Rating Scale for Depression (HAMD)-17, and/or self-administered questionnaires such as the Patient Health Questionnaire (PHQ)-9. However, these evaluation systems have relied on a person's subjective information, which sometimes lead to difficulties in clinical settings. To resolve this limitation, a more objective SOD evaluation system is needed. Herein, we collected clinical data including HAMD-17/PHQ-9 and blood plasma of psychiatric patients from three independent clinical centers. We performed metabolome analysis of blood plasma using liquid chromatography mass spectrometry (LC-MS), and 123 metabolites were detected. Interestingly, five plasma metabolites (3-hydroxybutyrate (3HB), betaine, citrate, creatinine, and gamma-aminobutyric acid (GABA)) are commonly associated with SOD in all three independent cohort sets regardless of the presence or absence of medication and diagnostic difference. In addition, we have shown several metabolites are independently associated with sub-symptoms of depression including SI. We successfully created a classification model to discriminate depressive patients with or without SI by machine learning technique. Finally, we produced a pilot algorithm to predict a grade of SI with citrate and kynurenine. The above metabolites may have strongly been associated with the underlying novel biological pathophysiology of SOD. We should explore the biological impact of these metabolites on depressive symptoms by utilizing a cross species study model with human and rodents. The present multicenter pilot study offers a potential utility for measuring blood metabolites as a novel objective tool for not only assessing SOD but also evaluating therapeutic efficacy in clinical practice. In addition, modification of these metabolites by diet and/or medications may be a novel therapeutic target for depression. To clarify these aspects, clinical trials measuring metabolites before/after interventions should be conducted. Larger cohort studies including non-clinical subjects are also warranted to clarify our pilot findings.

Maladaptive social interaction and its related psychopathology have been highlighted in psychiatry especially among younger generations. In Japan, novel expressive forms of psychiatric phenomena such as "modern-type depression" and "hikikomori" (a syndrome of severe social withdrawal lasting for at least six months) have been reported especially among young people. Economic games such as the trust game have been utilized to evaluate real-world interpersonal relationships as a novel candidate for psychiatric evaluations. To investigate the relationship between trusting behaviors and various psychometric scales, we conducted a trust game experiment with eighty-one Japanese university students as a pilot study. Participants made a risky financial decision about whether to trust each of 40 photographed partners. Participants then answered a set of questionnaires with seven scales including the Lubben Social Network Scale (LSNS)-6 and the Patient Health Questionnaire (PHQ)-9. Consistent with previous research, male participants trusted partners more than female participants. Regression analysis revealed that LSNS-family (perceived support from family) for male participants, and item 8 of PHQ-9 (subjective agitation and/or retardation) for female participants were associated with participants' trusting behaviors. Consistent with claims by social scientists, our data suggest that, for males, support from family was negatively associated with cooperative behavior toward non-family members. Females with higher subjective agitation (and/or retardation) gave less money toward males and high attractive females, but not toward low attractive females in interpersonal relationships. We believe that our data indicate the possible impact of economic games in psychiatric research and clinical practice, and validation in clinical samples including modern-type depression and hikikomori should be investigated.

Periodic auditory click stimulation has been reported to elicit an auditory steady state response (ASSR). The ASSR has been suggested to reflect the efficiency of γ-amino butyric acid (GABA) inhibitory interneuronal activity. Although a potential role for GABAergic dysfunction has been previously proposed, the role of neural synchronization in the ASSR in people with bipolar disorder (BD) has received little attention. In the current study, we investigated ASSRs to 20 Hz, 30 Hz, 40 Hz and 80 Hz click trains in BD patients. A total of 14 (4 males) BD patients and 25 (10 males) healthy controls participated in this study. ASSRs were obtained using whole-head 306-channel magnetoencephalography to calculate, ASSR power values and phase locking factors (PLF). BD patients exhibited significantly reduced mean ASSR power and PLF values bilaterally at frequencies of 30, 40, and 80 Hz (p

BACKGROUND: Microglia, one of the glial cells, play important roles in various brain pathologies including psychiatric disorders. In addition, microglia have recently been proved to monitor synaptic reactions via direct-touching even in normal brain. Human microglia may modulate various social/mental functions, while microglial social/mental roles remain unresolved especially in healthy humans. There is no known drug with the specific effect of modulating microglia. Therefore, using minocycline, a tetracycline antibiotic and the most famous microglial inhibitor, is one of the best alternative approaches to clarify microglial functions on human social/mental activities. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a double-blind randomized trial of trust game, a monetary decision-making experiment, with ninety-nine human adult males who decided how much to trust an anonymous partner after a four-day administration of minocycline. Our previous pilot trial indicated a positive effect of minocycline, while the underlying mechanisms were not clarified. Therefore, in this trial with larger samples, we additionally measured the effects of anxiety and personality. The monetary score in trust game was significantly lower in the minocycline group. Interestingly, participants' ways of decision-making were significantly shifted; cooperativeness, one component of personality, proved to be the main modulating factor of decision-making in the placebo group, on the other hand, the minocycline group was mainly modulated by state anxiety and trustworthiness. CONCLUSIONS/SIGNIFICANCE: Our results suggest that minocycline led to more situation-oriented decision-making, possibly by suppressing the effects of personality traits, and furthermore that personality and social behaviors might be modulated by microglia. Early-life events may activate human microglia, establish a certain neuro-synaptic connection, and this formation may determine each human's personality and personality- oriented social behaviors in later life. To explore these mechanisms, further translational research is needed. TRIAL REGISTRATION: UMIN clinical trial center UMIN000004803.