Reduced sociability in a prenatal immune activation model: Modulation by a chronic blonanserin treatment through the amygdala-hippocampal axis.

The environmental disturbances in a critical neurodevelopmental period exert organizational effects on brain intrinsic plasticity including excitatory and inhibitory (E/I) neurotransmission those can cause the onset of psychiatric illness. We previously reported that treatment of neural precursor cells with N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 induced reduction of GABAergic interneuron differentiation, and these changes recovered by atypical antipsychotic blonanserin treatment in vitro. However, it remains unclear how this treatment affects neural circuit changes in hippocampus and amygdala, which might contribute to the prevention of onset process of schizophrenia. To elucidate the pathogenic/preventive mechanisms underlying prenatal environmental adversity-induced schizophrenia in more detail, we administered poly (I:C) followed by antipsychotics and examined alterations in social/cognitive behaviors, GABA/glutamate-related gene expressions with cell density and E/I ratio, and brain-derived neurotrophic factor (Bdnf) transcript levels, particularly in limbic areas. Treatment with antipsychotic blonanserin ameliorated impaired social/cognitive behaviors and increased parvalbumin (PV)-positive (+) cell density and its mRNA levels as well as Bdnf with long 3'UTR mRNA levels, particularly in the dorsal hippocampus, in rats exposed to maternal immune activation (MIA). Low dose of blonanserin and haloperidol altered GABA and glutamate-related mRNA levels, the E/I ratio, and Bdnf long 3'UTR mRNA levels in the ventral hippocampus and amygdala, but did not attenuate behavioral impairments. These results strongly implicate changes in PV expression, PV(+) GABAergic interneuron density, and Bdnf long 3'UTR expression levels, particularly in the dorsal hippocampus, in the pathophysiology and treatment responses of MIA-induced schizophrenia and highlight the therapeutic potential of blonanserin for developmental stress-related schizophrenia.

Antidepressant activities of escitalopram and blonanserin on prenatal and adolescent combined stress-induced depression model: Possible role of neurotrophic mechanism change in serum and nucleus accumbens.

BACKGROUND: There has been number of studies suggesting experiences of adversity in early life interrelated subsequent brain development, however, neurobiological mechanisms confer risk for onset of psychiatric illness remains unclear. METHODS: In order to elucidate the pathogenic mechanisms underlying early life adversity-induced refractory depression in more detail, we administered corticosterone (CORT) to adolescent rats with or without prenatal ethanol exposure followed by an antidepressant or antipsychotic and examined alterations in depressive and social function behaviors and brain-derived neurotrophic factor (BDNF) levels in serum, the hippocampus, anterior cingulate cortex, and nucleus accumbens. RESULTS: The combined stress exposure of prenatal ethanol and adolescent CORT prolonged immobility times in the forced swim test (FST), and increased investigation times and numbers in the social interaction test (SIT). A treatment with escitalopram reversed depression-like behavior accompanied by reductions in BDNF levels in serum and the nucleus accumbens, while a treatment with blonanserin ameliorated abnormal social interaction behavior with reductions in serum BDNF levels. LIMITATIONS: Further studies are needed to clarify the clinical evinces responding to these results, and many questions remain regarding the mechanisms by which refractory depression and antidepressant/antipsychotic treatments cause changes in serum and brain regional BDNF levels. CONCLUSION: These results strongly implicate changes in BDNF levels in serum and the nucleus accumbens in the pathophysiology and treatment of early life combined stress-induced depression and highlight the therapeutic potential of escitalopram and new generation antipsychotic blonanserin for treatment-resistant refractory depression.

Psychiatric Consultations at an Emergency Department in a Metropolitan University Hospital in Northern Japan.

Many patients with mental disorders visit emergency departments (EDs). However, the majority of these patients do not receive psychiatric assessment. In the present study, we investigated the detailed proportion of patients with mental disorders visiting an urban ED in the largest northern city in Japan. A retrospective chart review study was performed at a University Hospital from January 2012 to December 2015. The reasons for psychiatric consultations made by ED staff, and the primary psychiatric diagnoses were investigated. Among all living patients, 20% of them received consultations. The most common reason for consultation was suicide attempt followed by agitation or insomnia. Of all diagnoses, organic mental disorder was the most frequent and the mean age was significantly higher than the other diagnostic groups. Our study indicated that the frequency of psychiatric consultation was high. This indicates the high demand for mental health services at the ED. A thorough psychiatric assessment can provide adequate psychiatric services to acute patients; thereby possibly preventing suicide attempters from later actually dying by suicide.

Prevalence rate of Internet addiction among Japanese college students: Two cross-sectional studies and reconsideration of cut-off points of Young's Internet Addiction Test in Japan.

AIM: Due to variation in estimates of the prevalence of Internet addiction (IA) in prior research, we conducted two cross-sectional studies over 2 years investigating the prevalence rate of IA in college students in Japan and reconsidered appropriate cut-off points of a self-rating scale to screen possible IA. METHODS: This study was composed of two parts: survey I in 2014 and survey II in 2016, which were conducted in the same schools with an interval of 2 years. The study questionnaire included questions about demographics and Internet use, and Young's Internet Addiction Test (IAT). Additionally, the subjects in survey II were asked about self-reported IA. RESULTS: There were 1005 respondents in total with a mean age (± SD) of 18.9 ± 1.3 years. The mean IAT scores remained stable between 2014 and 2016: 45.2 ± 12.6 in survey I and 45.5 ± 13.1 in survey II (overall mean IAT score of 45.4 ± 13.0). With respect to self-reported IA in survey II, a total of 21.6% admitted to having IA (score of 5 or 6 on a 6-point Likert scale). We categorized these subjects as IA, and the remainder as non-IA. The mean IAT score showed a significant difference between these two groups (57.8 ± 14.3 vs 42.1 ± 10.7, P < 0.001). CONCLUSION: The severity of IA symptoms among Japanese college students has appeared stable in recent years, with mean IAT scores of over 40. Our results suggest that a screening score cut-off of 40 on the IAT could be reconsidered and that 50 might be proposed for the cut-off.

Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development.

Internet addiction and self-evaluated attention-deficit hyperactivity disorder traits among Japanese college students.

AIM: Internet addiction (IA), also referred to as Internet use disorder, is a serious problem all over the world, especially in Asian countries. Severe IA in students may be linked to academic failure, attention-deficit hyperactivity disorder (ADHD), and forms of social withdrawal, such as hikikomori. In this study, we performed a survey to investigate the relation between IA and ADHD symptoms among college students. METHODS: Severity of IA and ADHD traits was assessed by self-report scales. Subjects were 403 college students (response rate 78%) who completed a questionnaire including Young's Internet Addiction Test (IAT) and the Adult ADHD Self-Report Scale-V1.1. RESULTS: Out of 403 subjects, 165 were male. The mean age was 18.4 ± 1.2 years, and mean total IAT score was 45.2 ± 12.6. One hundred forty-eight respondents (36.7%) were average Internet users (IAT < 40), 240 (59.6%) had possible addiction (IAT 40-69), and 15 (3.7%) had severe addiction (IAT ≥ 70). Mean length of Internet use was 4.1 ± 2.8 h/day on weekdays and 5.9 ± 3.7 h/day on the weekend. Females used the Internet mainly for social networking services while males preferred online games. Students with a positive ADHD screen scored significantly higher on the IAT than those negative for ADHD screen (50.2 ± 12.9 vs 43.3 ± 12.0). CONCLUSION: Our results suggest that Internet misuse may be related to ADHD traits among Japanese youth. Further investigation of the links between IA and ADHD is warranted.

Survey of the relationship between internet addiction and social withdrawal (HIKIKOMORI) in Japan.

PURPOSE: The Internet was originally designed to facilitate communication and research activities.'However, there has been a dramatic increase in the use of the Internet in recent years for commerce, education, and entertainment, including video games. Internet addiction as.a phenomena has been described by researchers as excessive or compulsive use of computers that interferes with daily life. Hikikomori (social withdrawal) -has increasingly become a problem in Japan and has been hypothesized to be ,related to internet, addiction. Particularly amongst students, problematic internet use may be a major factor of social withdrawal. We conducted a survey of internet addiction. and social- withdrawal among college students and corhpany workers to examine this hypothesis. METHODS: Subjects were 63 university students and 56 company workers. To examine the relationship between internet addiction and social withdrawal, we administered the Internet Addiction Test (IAT) and the UCLA Loneliness Scale (ULS), a measure of social isolation, to all subjects. RESULTS: Students tended to score higher than workers on the IAT (Student u = 36.3, Worker u = 31.1, p<0.05). For students considered addictive internet users, we found a significant correlation between the ULS and the IAT (r=0.549,. p<0.05); suggesting that social isolation and internet addiction are associated with each other. Workers tended to score higher on the ULS than students (Worker p =40.4, Student u =37.5, p<0.05). For workers .who were not addictive internet users, we found a'mild, negative correlation between the ULS and the IAT (r=- 0.285, p<0.05), suggesting that use of the internet for workers was not a compensatory behavior. CONCLUSIONS: Based upon the IAT, we found that more students than workers reported problems with internet use. Based upon.the ULS, more workers reported feelings of loneliness than students. Workers' loneliness did not appear to be related to their use of the internet, but amongst students with internet addiction, loneliness appeared to be associated with internet use.

Influence of comorbid alcohol use disorder on treatment response of depressive patients.

Patients with major depressive disorder (MDD) frequently also have alcohol use disorder (AUD) and they are more likely to experience symptomatic recurrence and resist treatment. How the two disorders interrelate has not yet been fully examined in Japanese subjects. The treatment response of 47 MDD patients was followed for 12 weeks. Depressive symptoms were rated by the 17-item Hamilton Rating Scale for Depression (HAM-D) and those whose HAM-D score was less than 16 were excluded. The MDD patients were divided into a non-alcohol use disorder (NAUD) and an alcohol use disorder (AUD) group according to the Alcohol Use Disorder Identification Test (AUDIT). We applied a cutoff score of 12 in the AUDIT scale. After 8 weeks, HAM-D NAUD group scores were significantly lower compared with AUD patients. The NAUD group, 23 individuals, prescribed therapeutic doses of antidepressant (equivalent to more than 150 mg of imipramine per day) significantly improved their HAM-D scores but no improvement occurred in the AUD subjects. Correlation analysis in all subjects revealed a significant negative correlation between AUDIT score and improved HAM-D score at endpoint. Moreover, a significant negative correlation was found between total alcohol consumption during the study period and improvement of HAM-D score at endpoint in AUD patients. These results suggest that co-occurrence of MDD and AUD is associated with a lower response to antidepressant treatment and it may reflect an inhibitory effect of ethanol on antidepressants action in the brain.

[Treatment response of depressive patients with comorbid problem drink].

In this study, we investigated the impact of Problem Drink on depression. Forty participants with depression were divided into 2 groups: non-Problem Drinker (NPD) group (n = 22) and Problem Drinker (PD) group (n = 18) according to Alcohol Use Disorder Identification Test (AUDIT) score (NPD < 12, PD > or = 12). Depression was assessed by the Mini-International Neuropsychiatric Interview. The effect of medication on depressive symptoms was monitored over 12 weeks using the Hamilton Rating Scale for Depression (HAM-D). Significant improvement in HAM-D score was observed at 2 weeks in NPD patients but not until 4 weeks in PD patients. Total HAM-D scores were lower in NPD than in PD patients at the end of the treatment period. Therapeutic doses (dose of antidepressant used was equivalent to greater than 75 mg of imipramine) of antidepressants resulted in significant improvement in HAM-D scores at 2 weeks in NPD patients, but not until 8 weeks in PD patients and brought lower HAM-D scores in NPD than in PD patients at the end of the treatment period. The AUDIT score and total alcohol consumption during the study period were negatively correlated to the improvement in HAM-D score. In NPD patients, the level of education of patients in remission was higher than those by patients not in remission. In contrast, level of education of patients in remission were similar to those in PD patients not in remission. The above results suggest that co-occurrence of alcohol use disorders with depression is associated with a lower response to antidepressants which may reflect not only the result of biological alterations in the brain by chronic ethanol ingestion but also an inhibitory effect of ethanol on antidepressant action in the brain. Drinking-related cognitive dysfunction may also relate to the decreased response to treatment in the depressed patients with comorbid Problem Drinker.

The study of cognitive characteristics in Asperger's disorder by using a modified Prisoner's Dilemma game with a variable payoff matrix.

Individuals with Asperger's Disorder (ASP) have difficulties in social reciprocity and in providing appropriate cooperative behavior. The Prisoner's Dilemma (PD) is a well-known model in game theory that illustrates the paradoxical disposition of interaction between two individuals with opposing interests, and may be a useful tool in the diagnosis of ASP in early childhood. In this study, we investigated the cognitive characteristics of ASP by using a modified PD game. The subjects were 29 individuals with ASP and 28 age- and IQ-matched controls. In the PD game, each of two players has two cards: card 1 represents cooperation and card 2 betrayal. The score each player obtains is decided according to a 2 x 2 payoff matrix and depends on the combination of their selections. The P-score ("P" for punishment) is defined as the score that is given when they both select betrayal. Comparing the two groups, the mean P-score at the end of the game and the mean total score were significantly higher in the ASP group, while the rate of selection of cooperative choice in both groups did not differ significantly. The classification of the shape of the graph according to fluctuation of the P-score revealed that in the ASP group only 2 cases (6.9%) showed continuous decrease of P-score compared to 8 control cases (28.6%) demonstrating similar results. However, the reasons were thought to be different: ASP subjects presumably selected card 2 because of a preference for the number itself, whereas control subjects preferentially chose this card to enhance their chance of winning the competition. It is often difficult to diagnose ASP in the young especially when they lack the distinctive clinical features of ASD in early childhood. Given the limited number of objective tools to evaluate the cognitive characteristics of ASP subjects, the PD game might be a useful diagnostic support tool for ASP.