新津 富央

The complex pathophysiology of treatment-resistant schizophrenia (TRS) includes severe positive symptoms but also other symptom domains. The overlapping psychological profiles of schizophrenia and autistic spectrum disorder (ASD) are not established. We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on both neurodevelopmental aspects and general and social cognitive impairments. The TRS group performed the worst on general neurocognition (measured by the MATRICS Consensus Cognitive Battery) and social cognition (measured by the theory of mind and emotional expression). The RemSZ group performed the best among the three groups. Regarding autistic traits, all measurements by the Autism-Spectrum Quotient/Autism Screening Questionnaire/Pervasive Developmental Disorder Assessment Rating Scale showed that (1) the ASD patients had the highest autistic traits (2) the TRS patients' scores were less severe than the ASD group's, but (3) the overall trends placed the TRS group between the ASD and the RemSZ group. These findings indicate that TRS patients and remitted patients could have distinctive neurodevelopmental and cognitive profiles. Further, the degrees of social cognitive dysfunction and autistic traits in TRS patients could be close to those of ASD patients, suggesting similarities between TRS and ASD.

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.

<title>Abstract</title> <bold>Objective:</bold> The coronavirus disease 2019 pandemic has caused school closures worldwide. Japan's Prime Minister declared a state of emergency based on the coronavirus pandemic for Tokyo, Chiba, and other prefectures on April 7, 2020. Children with ADHD are particularly vulnerable to the distress caused by the pandemic and physical distancing measures, and they might display increased behavioral problems. We surveyed 15 children with ADHD, aged 11.8 ± 2.8 years old; 13 were males and 2 were females (combined subtype, n=12; inattentive subtype, n=3). The children's ADHD-RS scores were assessed by their mother (n=12), father (n=1), or nursing home staff (n=2) from before the emergency declaration (in February or March 2020) to after the emergency declaration (April or May 2020). There were no changes of treating physician, drug type or quantity, or psychotherapy or assessment person from January 2020 to May 2020. <bold>Results:</bold> A comparison of the baseline scores and secondary outcomes reveals that the ADHD-RS total score and inattentive subscore worsened significantly during this period, whereas the hyper/impulsive subscore did not. In conclusion, we suggest that policymakers, healthcare providers and families should be mindful of the potential development of inattentiveness among children with ADHD who are quarantined because of COVID-19.

Background: The novel corona virus infection (COVID-19) quickly became a pandemic state. Identifying characteristics of "possible super spreaders", suggested as a dominant cause of rapid spreading transmission, will help us to design proper prevention strategies. Methods: We conducted a nation-wide online survey to investigate the relationship of perception and anxiety levels about COVID-19 to the possible risk behaviors for spread of the virus in Japan. We recruited a total of 4,000 citizens, who responded to the questionnaire including several questions regarding the level of fear and anxiety about COVID-19, infection preventive behaviors and access to media with trust level about the virus as well as some demographic and socioeconomic data during March 27th and 28th, 2020. Findings: Thirteen-point-three percent of the participants rated "1" on a nine-point Likert with respect to the knowledge about COVID-19. Ten-point-one percent and 11.7% presented no anxiety of being infected and transmission to others. Ten-point-eight percent showed no worry about symptomatic aggravation. Eight-point-one percent had no serious concern about expanding infection. The distribution of these items was highly correlated with each other. Participants with the low level of knowledge about COVID-19 were likely to less frequently access any information sources and neither trust them. They were less anxious about their health status, and less likely to put precautionary behaviors such as washing hands and avoiding crowded spaces, suggested by statistical analyses. Interpretation: The present study suggests that it is greatly important to enlighten those have no concerns about this crisis of COVID-19 and modify their risk behavior via various ways, in order to prevent and control this viral pandemic. Funding: This study was funded by the management grand provided to Chiba University Graduate School of Medicine and the Japan Society for the Promotion of Science KAKENHI grants.

AIM: Matrix metalloproteinase-9 (MMP-9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP-9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP-9 in pathophysiology of schizophrenia, especially in cognitive decline. METHODS: We measured the plasma levels of MMP-9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug-free patients. We also explored the possible association between plasma MMP-9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS- III), the Wechsler Memory Scale-Revised (WMS-R), and the Rey Auditory Verbal Learning Test (AVLT). RESULTS: We found that the plasma levels of MMP-9 were significantly higher in patients with schizophrenia, including antipsychotic drug-free patients, than in healthy controls. We found a significant negative association between plasma MMP-9 levels and cognitive performance in controls and patients with schizophrenia. CONCLUSION: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP-9 levels are associated with cognitive impairment.

We describe the case of a 49-year-old Japanese male patient successfully treated with a paliperidone rechallenge following 2-year treatment with clozapine for treatment-resistant schizophrenia. He had responded well to conventional antipsychotic treatment for the initial psychotic episode but gradually developed dopamine supersensitivity; even treatment with paliperidone and another antipsychotic medication (a total up to 1700 mg in chlorpromazine-equivalent dose) had not improved his psychotic symptoms. Clozapine treatment produced temporary symptomatic relief, but the clozapine dose could not be increased to > 150 mg due to the patient's intolerance. Following low-dose clozapine treatment for 2 years, a rechallenge with paliperidone monotherapy ameliorated his psychotic symptoms. This suggests that clozapine may have the potential to release the dopamine supersensitivity state. Our patient's case indicates that for patients with dopamine supersensitivity psychosis, a rechallenge with a previously ineffective antipsychotic after clozapine treatment may be successful.

Background: An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. Methods: We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale-Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. Results: We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment.

Bakground: Patients with behavioral disorders following severe traumatic brain injury (sTBI) often have disorders of consciousness that make expressing their emotional distress difficult. However, no standard method for assessing the unsettled and unforeseen responses that are associated with behavioral disorders has yet to be established. Because the thalamus is known to play a role in maintaining consciousness and cognition, we used 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to examine the association between brain glucose metabolism in the thalamus and behavioral disorders. Methods: We retrospectively analyzed 70 consecutive patients with sTBI who had been involved in motor vehicle accidents. To assess behavioral disorders, we evaluated 18 symptoms using the Brief Psychiatric Rating Scale (BPRS): Emotional Withdrawal, Conceptual Disorganization, Tension, Mannerisms and Posturing, Motor Retardation, Uncooperativeness, Blunted Affect, Excitement, Somatic Concern, Anxiety, Feeling of Guilt, Grandiosity, Depressive Mood, Hostility, Suspiciousness, Hallucinatory Behavior, Unusual Thought Content, and Disorientation. First, we identified clinical characteristics of sTBI patients with behavioral disorders. Next, we retrospectively analyzed 18F-FDG-PET/CT data to assess how thalamic activity was related with abnormal behaviors. Results: Twenty-six patients possessed the minimum communicatory ability required for psychiatric interview. Among them, 15 patients (57.7%) were diagnosed with behavioral disorder, 14 of whom had reached a stable psychiatric state after about 426.6 days of treatment. Excitement (13 patients) and uncooperativeness (10 patients) were the most frequently observed symptoms. Available 18F-FDG-PET/CT data indicated that thalamic glucose metabolism was imbalanced and lateralized (p = 0.04) in 6 patients who exhibited uncooperativeness. Conclusions: Behavioral symptoms of excitement and uncooperativeness were common in patients with sTBI, although most symptoms improved as the chronic stage continued. Our data support the idea that imbalanced laterality of glucose metabolism in the thalamus might be related to behavioral disorders characterized by uncooperativeness. Trial registration: UMIN 000029531. Registered 27 March 2017, retrospectively registered.

Stressful life events, although less serious than traumatic experiences, affect the clinical course of patients with bipolar disorder. We previously found that bipolarity in patients with major depression is related to the severity of psychological distress symptoms associated with onset-related events. Here, we investigated whether, and to what extent, bipolar patients perceive stressful events as psychological distress symptoms, specifically, intrusion, avoidance, and hyperarousal. Further, we investigated the relationship between the clinical features and the severity of psychological distress symptoms associated with stressful life events, according to mood states. We recruited 79 bipolar patients (depression group, n = 32; mania, n = 22; euthymia, n = 25) in this cross-sectional study. We adopted the Impact of Event Scale-Revised (IES-R) to assess the severity of psychological distress symptoms associated with past stressful events. We also evaluated the Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). The mean (standard deviation) IES-R scores of bipolar patients with a depressive episode (38.06 [16.56], p = 0.0005) and of those with a manic/hypomanic episode (44.56 [24.14], p = 0.004) were significantly higher than of those with euthymia (19.81 [12.86]). The HDRS, but not the YMRS, scores showed significant correlations with the IES-R scores, regardless of mood episodes (depression group, r = 0.42; mania, r = 0.64; euthymia, r = 0.70). This study demonstrates that bipolar patients with a manic/hypomanic or depressive episode perceive stressful life events as more severe psychological distress symptoms than do euthymic patients. Moreover, in patients with bipolar disorder, the severity of depressive symptoms, but not of manic symptoms, is positively correlated with that of the psychological distress symptoms, regardless of their mood episodes or euthymic state. Therefore, depressive symptoms may be closely related to the psychological distress symptoms associated with stressful past events in patients with bipolar disorder.

BACKGROUND: A significant portion of patients with schizophrenia who respond to initial antipsychotic treatment acquire treatment resistance. One of the possible pathogeneses of treatment-resistant schizophrenia (TRS) is antipsychotic-induced dopamine supersensitivity psychosis (Ai-DSP). Patients with this disease progression might share some genetic vulnerabilities, and thus determining individuals with higher risks of developing Ai-DSP could contribute to preventing iatrogenic development of TRS. Therefore, we decided to examine whether combinations of functional single nucleotide polymorphisms (SNPs) known to affect dopaminergic functions are related to Ai-DSP development. METHODS: In this case-control study, 357 Japanese participants diagnosed with schizophrenia or schizoaffective disorder were recruited and divided into two groups, those with and without Ai-DSP. As functional SNPs, we examined rs10770141 of the tyrosine hydroxylase gene, rs4680 of the catechol-O-methyltransferase gene, and rs1799732 and rs1800497 of the DRD2 genes, which are known to possess strong directional ties to dopamine synthesis, dopamine degradation and post-synaptic DRD2 prevalence, respectively. RESULTS: Among the 357 Japanese patients with schizophrenia or schizoaffective disorder, 130 were classified as Ai-DSP(+) and the other 227 as Ai-DSP(-). Significantly higher proportions of Ai-DSP(+) patients were found to have the SNP combinations of rs10770141/rs4680 (57.9%, OR2.654, 95%CI1.036-6.787, P = 0.048) and rs10770141/rs4680/ rs1800497 (64.3%, OR4.230, 95%CI1.306-13.619, P = 0.029). However, no single SNP was associated with Ai-DSP. CONCLUSIONS: We preliminarily found that carrying particular combinations of functional SNPs, which are related to relatively higher dopamine synthesis and dopamine degradation and lower naïve DRD2, might indicate vulnerability to development of Ai-DSP. However, further studies are needed to validate the present results.

AIM: To evaluate the effect of educational intervention on individuals' knowledge of and attitudes toward forensic mental health. METHODS: We conducted a questionnaire regarding attitudes toward various ideas about forensic mental health. The respondents attended a 1-h seminar regarding forensic mental health after answering the questionnaire. On completion of the seminar, the respondents answered another questionnaire containing many of the same questions as contained in the pre-seminar questionnaire. RESULTS: A total of 86 individuals attended the seminar, and 78 responded to the questionnaire. Only 13 (18.8%) participants were supportive of the concept of criminal responsibility initially, and there was a statistically significant increase in those who became more supportive after the seminar, with 22 (33%) being supportive after the seminar (Wilcoxon signed-rank test, P < 0.001). Logistic regression analysis revealed that participants who were skeptical about forensic mental systems and those with fewer opportunities to see media reports regarding psychiatry were likely to become supportive of criminal responsibility after the intervention. CONCLUSION: These results suggest that public attitudes toward criminal responsibility and mental health can be influenced via educational interventions.

BACKGROUND: The long-term administration of antipsychotics is known to induce dopamine supersensitivity psychosis (DSP). Although the mechanism of DSP involves mainly a compensatory upregulation of dopamine D2 receptors, the precise mechanisms underlying DSP are unknown. It is known that glutamatergic signaling plays a key role in psychosis. We thus conducted this study to investigate whether glutamatergic signaling plays a role in the development of DSP. METHODS: Haloperidol (0.75 mg/kg/day for 14 days) or vehicle was administered to rats via osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSP rats and non-DSP rats based on locomotion data. Tissue levels of glutamate, glutamine, glycine, L-serine, D-serine, and GABA and the protein expressions of N-methyl-D-aspartate receptors (NMDAR), glutamic acid decarboxylase (GAD), and serine hydroxymethyltransferase (SHMT) in the rat brain regions were examined. RESULTS: In the DSP rats, the ratio of GABA to glutamate was significantly increased. In addition, the ratio of L-serine to glycine was increased. The striatal expressions of GAD and SHMT2 in the DSP rats were significantly increased. In contrast, the striatal expression of NMDAR2B in the non-DSP rats was significantly decreased. CONCLUSIONS: The present study suggests that glutamatergic signaling is relatively decreased to GABA in DSP rats. Our results also showed that excessive doses of haloperidol can induce striatal NMDAR hypofunction in non-DSP rats, which could prevent the formation of tardive dyskinesia but cause treatment resistance. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, further research exploring our present findings is necessary.

Aim: The aims of this study were to determine whether the serum levels of precursor brain-derived neurotrophic factor (proBDNF), mature BDNF (mBDNF), and matrix metalloproteinase-9 (MMP-9) are altered in patients with eating disorders (ED), including anorexia nervosa (AN) and bulimia nervosa (BN), and to explore whether those levels are associated with decision-making abilities. Methods: Nineteen women with AN, 28 women with BN, and 22 age-matched healthy control women (HC) were enrolled in the current study. All participants had their decision-making abilities assessed using the Iowa Gambling Task (IGT). Their eating-related pathophysiology and depressive/anxiety symptoms were also evaluated. Results: The MMP-9 level in AN was significantly lower than that in either BN or HC, but the serum levels of proBDNF and mBDNF did not differ among the three groups. Investigation of the serum levels of proBDNF and MMP-9 in patients with ED and controls revealed a significant correlation between them. In the BN, there were positive correlations between mBDNF level and IGT performance and also between MMP-9 level and IGT performance, but these correlations did not occur in AN. The MMP-9 level was positively associated with the Symptom Scale, one of the subscales of the Bulimic Investigatory Test, Edinburgh, only in AN. Conclusion: These results suggest that the serum level of MMP-9 plays a role in the pathophysiology of AN, and both the serum levels of mBDNF and MMP-9 may be associated with decision-making abilities in patients with BN.

Objective Dopamine supersensitivity psychosis (DSP) is one of the key factors contributing to the development of antipsychotic treatment-resistant schizophrenia (TRS). We investigated the efficacy of blonanserin, an atypical antipsychotic, for patients with TRS and DSP. Methods In this 12-month retrospective follow-up study, we investigated the cases of eight consecutive patients with unstable TRS and DSP treated with blonanserin as an add-on therapy. We examined changes in scores for the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression-Severity of Illness (CGI-S) scale and the Global Assessment of Functioning scale (GAF) during the 12 months after the administration of blonanserin. Results The patients’ total scores on the BPRS and GAF scores were significantly improved by 3 months at the latest. Positive BPRS and CGI-S scores were also improved by 6 months at the latest. The total chlorpromazine-equivalent doses of antipsychotics were significantly reduced from 1462.3 ± 499.6 mg to 794.1 ± 642.8 mg (p = 0.001) after 12 months of blonanserin treatment, with a favorable safety and tolerability profile. Conclusions Blonanserin may be a promising antipsychotic for the treatment of TRS and DSP.

Background: This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. Methods: We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a &gt;= 50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. Results: Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P &lt; 0.001; and 12.5 vs. 81.8 %, P = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased (chi(2) = 8.5, df = 3, P = 0.036) and serum mature BDNF levels were temporarily significantly decreased (F = 3.5, df = 2.4, P = 0.027) in the responders of both groups at week 24. Conclusion: This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled

Background: The lowering of the age of onset and chronicity have been key problems related to eating disorders (EDs). As the proportion of teens in the estimated onset ages has increased, it has become important to detect students with EDs and to clarify how they can be supported. Though epidemiological surveys of Yogo teachers (school nurse/health science teachers) have been conducted to inquire about the number of such students, none of these were done according to ED type based on DSM-5. Thus, we conducted a wide area survey in Japan with the goal of proposing a better framework of support for Yogo teachers in their efforts to care for students with EDs. Methods: A questionnaire survey organized by ED type (based on DSM-5) was administered to Yogo teachers working at elementary/junior high/senior high/special needs schools in four prefectures of Japan in 2015, and 1,886 responses were obtained. Based on the results, the encounter rates (the proportion of Yogo teachers who had encountered a student with an ED) were calculated, and factors that could affect the rates were examined by logistic regression analysis. Results: The order of the encounter rates of the ED types was as follows: Anorexia Nervosa (AN) &gt; Bulimia Nervosa (BN) &gt; Avoidant/Restrictive Food Intake Disorder (ARFID) &gt; Binge Eating Disorder (BED) &gt; Others. The factors significantly affecting the rates were "location, school type, number of students, experience years, and AN knowledge" for AN, "school type, experience years, and BN knowledge" for BN, "school type, experience years, and BED knowledge" for BED, "location, experience years, and ARFID knowledge" for ARFID, and "school type, experience years, and Others knowledge" for Others. Conclusions: Because the encounter rate of AN was the highest, providing support for AN would be the most effective. Moreover, one factor that affected the encounter rate of all ED types was ED knowledge. In addition to this, senior high schools had the highest encounter rates for AN, BN and BED, and special needs schools had the highest rates for Others. These findings imply that, in order to detect and support ED students at an early stage, it is necessary to offer knowledge of the most prevalent ED types to Yogo teachers at the corresponding school type.

Objective 'Treatment-resistant depression' is depression that does not respond to an adequate regimen of evidence-based treatment. Treatment-resistant depression frequently becomes chronic. Children with treatment-resistant depression might also develop bipolar disorder (BD). The objective of this study was to determine whether serum levels of oxytocin (OXT) in treatment-resistant depression in adolescents (TRDIA) differ from non-treatment-resistant depression in adolescents (non-TRDIA) or controls. We also investigated the relationships between serum OXT levels and the clinical symptoms, severity, and familial histories of adolescent depressive patients. Methods We measured serum OXT levels: TRDIA (n = 10), non-TRDIA (n = 27), and age-and sex-matched, neurotypical controls (n = 25). Patients were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and the Depression Self-Rating Scale for Children-Japanese Version (DSRS-C-J). The patients were also assessed retrospectively using the following variables: familial history of major depressive disorder and BD (1st degree or 2nd degree), history of disruptive mood dysregulation disorder, recurrent depressive disorder (RDD), history of antidepressant activation. Results Serum levels of OXT among the TRDIA and non-TRDIA patients and controls differed significantly. Interestingly, the rates of a family history of BD (1st or 2nd degree), RDD and a history of antidepressant activation in our TRDIA group were significantly higher than those of the non-TRDIA group. Conclusions Serum levels of OXT may play a role in the pathophysiology of TRDIA.

Objective Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. Method We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). Results Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p&lt 0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p&lt 0.001). Conclusion This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.

Background: Although antidepressants are still a commonly used treatment for social anxiety disorder (SAD), a significant proportion of patients fail to remit following antidepressants. However, no standard approach has been established for managing such patients. This study aimed to examine the effectiveness of cognitive behavioral therapy (CBT) as an adjunct to usual care (UC) compared with UC alone in SAD patients who remain symptomatic following antidepressant treatment. Methods: This was a prospective randomized open-blinded end-point study with two parallel groups (CBT + UC, and UC alone, both for 16 weeks) conducted from June 2012 to March 2014. SAD patients who remain symptomatic following antidepressant treatment were recruited, and a total sample size of 42 was set based on pilot results. Results: Patients were randomly allocated to CBT + UC (n = 21) or UC alone (n = 21). After 16 weeks, adjusted mean reduction in the Liebowitz Social Anxiety Scale from baseline for CBT + UC and UC alone was -40.87 and 0.68, respectively; the between-group difference was -41.55 (-53.68 to -29.42, p &lt; 0.0001). Response rates were 85.7 and 10.0% for CBT + UC and UC alone, respectively (p &lt; 0.0001). The corresponding remission rates were 47.6 and 0.0%, respectively (p = 0.0005). Significant differences were also found in favor of CBT + UC for social anxiety symptoms, depressive symptoms, and functional impairment. Conclusions: Our results suggest that in SAD patients who have been ineffectively treated with antidepressants, CBT is an effective treatment adjunct to UC over 16 weeks in reducing social anxiety and related symptoms. (C) 2016 The Author(s) Published by S. Karger AG, Basel

Attention Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorder (ASD) are highly comorbid, and both disorders share executive function deficits. Accumulating evidence suggests that ASD patients have significantly lower peripheral oxytocin (OXT) levels compared with their normal counterparts, and that the repetitive behavior seen in ASD is related to abnormalities in the OXT system. In this study, we investigated whether serum levels of OXT are altered in pediatric patients with ADHD. We measured serum OXT levels: drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22). Patients were evaluated using the ADHD-RS. Serum levels of OXT in total subjects with ADHD were significantly decreased compared with those of neurotypical controls, and serum levels of OXT in drug naive ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum OXT levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients. In conclusion, this study suggests that decreased levels of OXT may play a role in the pathophysiology of patients with ADHD and its inherent inattentiveness. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

Manic switch is a relevant issue when treating bipolar depression. Some risk factors have been suggested, but unequivocal findings are lacking. We therefore investigated predictors of switch from depression to mania in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) sample. Manic switch was defined as a depressive episode followed by a (hypo)manic or mixed episode within the following 12 weeks. We assessed possible predictors of switch using generalized linear mixed models (GLMM). 8403 episodes without switch and 512 episodes with switch (1720 subjects) were included in the analysis. Several baseline variables were associated with a higher risk of switch. They were younger age, previous history of: rapid cycling, severe manic symptoms, suicide attempts, amphetamine use and some pharmacological and psychotherapeutic treatments. During the current depressive episode, the identified risk factors were: any possible mood elevation, multiple mania-associated symptoms with at least moderate severity, and comorbid panic attacks. In conclusion, our study suggests that both characteristics of the disease history and clinical features of the current depressive episode may be risk factors for manic switch. (C) 2015 Elsevier Ltd. All rights reserved.

Background: Previous studies have reported that various non-life-threatening life events could cause psychological distress symptoms like posttraumatic stress disorder in adults and adolescents. We examined whether patients with treatment-refractory depression (TRD) perceive their experiences of life events, of which they think as triggering the onset of depression, as more serious psychological distress symptoms than remitted or mildly symptomatic patients with major depressive disorder (MOD). Methods: This study employed a cross-sectional design. We recruited 78 outpatients consisting 0131 TRD patients, 31 remitted MOD patients, and 16 mildly symptomatic MOD patients. We adopted the Impact of Event Scale-Revised (IES-R) to assess the severity of psychological distress symptoms associated with the events that patients thought as triggering the onset of depression. We also evaluated clinical features and variables including the Hamilton Depression Rating Scale (HORS). Results: The mean [+/- SD] score of the IES-R in patients with TRD (46.7 [15.11) was significantly higher than in remitted (10.3 19.91, p &lt; 0.001) or mildly symptomatic (31.3 [17.7], p &lt; 0.001) patients with MOD. The HORS scores showed significant correlations with those of the IES-R among all patients (r=0.811). Limitations: This study was not able to exclude the possibility that the severity of psychological distress symptoms associated with onset-related events could influence the difficult therapeutic course in patients with TRD clue to the cross-sectional design. Conclusions: This study demonstrated that patients with TRD perceive their onset-related life events as serious psychological distress symptoms. This result contributes to understanding the pathophysiology of TRD. (C) 2015 Elsevier B.V. All rights reserved.

Background: Defective decision-making is a symptom of impaired cognitive function observed in patients with schizophrenia. Impairment on the Iowa Gambling Task (IGT) has been reported in patients with schizophrenia, but these results are inconsistent among studies. Methods: We differentiated subjects based on whether they expressed certainty at having deciphered an advantageous strategy in the course of the task. We investigated this impairment using the IGT in patients with schizophrenia and performed analysis different to standard advantageous decks minus disadvantageous decks in all 100 card choices, [C+D]-[A+B](1-100). We examined the effects on behavior after receiving a big penalty. Results: Results were dependent on participants utilizing with or without certainty, the best strategy for positive gain. Schizophrenic patients without certainty failed to show card choice shift, from disadvantageous to advantageous decks. Differences in card choices on the IGT were clearly shown between patients with schizophrenia and normal controls by the use of improvement from block 1 to blocks 3-5, [C+D]-[A+B]([41-100]-[1-20]) (P &lt; 0.001), rather than by the composite value of blocks 3-5, [C+D]-[A+B](41-100) (P = 0.011). The deficit of emotion-based learning in schizophrenia without uncertainty were related to scores on the SANS and S5 attention. In addition, S1 affective flattering and S4 anhedonia-asociality were also related to these deficits. For a while, normal controls showed a smooth shift from disadvantageous to advantageous decks after big penalties, with orwithout a certainty for strategy. However, patients with schizophrenia failed to show switching from disadvantageous to advantageous decks, even after big penalties, under the same conditions. Conclusions: Our results highlight certainty of strategy and behavior after a big penalty, as two points of difference between patients with schizophrenia and normal controls in the accumulation of net scores. (C) 2014 Elsevier Inc. All rights reserved.

Accumulating evidence suggests that patients with schizophrenia are exposed to a high risk of osteoporosis/osteopenia caused by long-term antipsychotic treatment. The degree of bone mineral density (BMD) loss that a given antipsychotic may cause is not known. Examinations using a bone turnover marker may more accurately predict the ongoing bone states in psychiatric patients. We measured prolactin, estradiol, testosterone, and bone resorption marker (TRACP-5b) levels in 167 patients with schizophrenia and 60 normal controls. The patients showed significantly higher levels of prolactin and lower levels of TRACP-5b compared to the controls. Moreover, prolactin was negatively correlated with estradiol and testosterone in the group of all male subjects and the male patients. TRACP-5b was positively correlated with prolactin in the female patients and negatively correlated with estradiol in the group of all female subjects. The results show that the bone resorption rate was rather attenuated in the patients compared to the normal controls, suggesting a complicated etiology of BMD loss in schizophrenia patients. Several meaningful correlations between key factors in this study confirmed that hyperprolactinemia induced the suppression of sex hormones, and possibly led to the higher bone turnover. These results indicate that measurement of the resorption marker TRACP-5b might be useful to clarify the pathology of BMD loss. (C) 2014 Elsevier B.V. All rights reserved.

Introduction: The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues. Areas covered: The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p &lt; 0.0001) outlined by previous GWAS in order to identify possible molecular mechanisms involved in SSRI effect. Expert opinion: In order to improve the understanding of SSRI pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.

Several lines of evidence suggest that glial cell-line derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric and neurodegenerative disorders. In this study, we investigated the association between GDNF serum levels and the clinical status of medicated patients with schizophrenia. Sixty-three medicated patients with schizophrenia and 52 age- and sex-matched healthy controls were recruited. Patients were evaluated using the brief psychiatry rating scale, the scale for the assessment of negative symptoms (SANS) and neuropsychological tests. Serum levels of GDNF were determined using an ELISA method. Serum levels of GDNF did not differ between schizophrenia patients and controls. Higher GDNF serum levels were associated with better performances on the Digit Span in healthy controls but not in schizophrenics. At the same time, higher GDNF serum levels were associated with severe attention deficits on the SANS subscale, in schizophrenics. Our preliminary study suggests that serum levels of GDNF may be an unsuitable biomarker for schizophrenia, although it may be associated with working memory in healthy controls and the pathophysiology of attention deficits in schizophrenia. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Background: The psychological impact of dual-disasters (earthquakes and a nuclear accident), on affected communities is unknown. This study investigated the impact of a dual-disaster (earthquakes and radioactive contamination) on the prevalence of psychological distress in a landlocked city within the Tohoku area, Japan. Methods. A cross-sectional mail-in survey with a random sample of inhabitants from Ichinoseki city was conducted eleven months after the disasters, and data from 902 respondents were analyzed by logistic regression models, with multiple imputation methodology. The K6 was used to determine psychological distress. Results: The estimated prevalence of psychological distress was 48.0 percent. House damage due to earthquakes and anxiety about radioactive contamination were significantly associated with psychological distress (p &lt 0.05), while an interactive effect between house damage and anxiety about radioactive contamination was not significant. Being female, middle-to-low educational status and unemployed were additional risk factors for psychological distress. Conclusions: This dual-disaster was associated with a moderate prevalence of psychological distress in the area. The impact of the earthquake and radioactive contamination appeared additive. © 2014Niitsu et al. licensee BioMed Central Ltd.

A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

A number of candidate gene studies focused on major depression (MD) and antidepressant (AD) efficacy have been carried out, but results mainly remain inconclusive. We performed a comprehensive meta-analysis of published candidate gene studies focused on AD efficacy in MD to evaluate the cumulative evidence. A random-effect model was applied to study the polymorphisms with genotypic counts available from at least three independent studies. On the base of previous evidence, the analysis was stratified by ethnicity (Caucasian, Asian, and other/mixed), and AD class (SSRIs and mixed/other ADs).Genotypic data were available for 16 polymorphisms in 11 genes. After the exclusion of 5-HTTLPR in SLC6A4 included in another recent meta-analysis, 15 polymorphisms in 11 genes were included in the present meta-analysis (BDNF rs6265, SLC6A4 STin2, HTR1A rs6295, HTR2A rs6311, rs6313 and rs7997012, HTR6 rs1805054, TPH1 rs1800532, SLC6A2 rs5569, COMT rs4680, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs1045642 and rs2032582).Our results suggested that BDNF rs6265 (Val66Met) heterozygous genotype was associated with better SSRIs response compared to the homozygous genotypes, particularly in Asians (OR=1.53, 95%CI 1.12-2.07, p=0.007). SLC6A4 STin2, HTR2A rs6311 and rs7997012, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs2032582 showed associations with AD efficacy, but these results were highly dependent on one or two single studies.In conclusion, our findings suggested the BDNF Val66Met as the best single candidate involved in AD response, with a selective effect on SSRI treatment. Our overall results supported no major effect of any single gene variant on AD efficacy. © 2013 Elsevier Inc.

Several studies have proposed an optimal dopamine D2 receptor occupancy by antipsychotics (OOc) to establish optimal pharmacological treatment of schizophrenia. However, there are limitations to the use of the OOc, especially in application to patients with treatment-resistant schizophrenia, including dopamine supersensitivity psychosis (DSP) or late-onset psychosis (LOP). It has been suggested that D2 receptor density is up-regulated by chronic treatment of antipsychotics in DSP, whereas it may be low in LOP owing to age-related reduction. In estimation of the proposed OOc, these alterations have not been taken into account, which may be one of the factors contributing to the limited application of this index. We here hypothesize that there is an optimal range in the number of D2 receptors available for dopamine binding to elicit adequate neurotransmission in the treatment of patients with schizophrenia. We then estimated the OOc under the assumption that the range is constant while D2 density is variable. The results showed that the OOc and plasma level of antipsychotics increase with an increase in the D2 density but decrease with a decrease in the D2 density. That is, if the range of OOc is 65% to 78% in a standard D2 density, it becomes 82% to 89% under 2-fold up-regulated density and 42% to 63% under a 40% reduced density. The results also indicated that the reduction of the plasma antipsychotic level is greater during a given time period in patients with higher D2 density, as they need a higher antipsychotic dose to achieve the raised OOc, which would account for the clinical features of DSP, for example, acute exacerbation after a discontinuation of antipsychotics. On the other hand, in patients with lower D2 density, only a lower antipsychotic dose will achieve the OOc, and a small increase in the dose will result in a greater increase in occupancy and induce extrapyramidal adverse effects more easily. Furthermore, the reduction of the plasma antipsychotic level during the time period is smaller, which prolongs extrapyramidal adverse effects after discontinuation of antipsychotics in LOP. We also attempted to develop a strategy for the prevention and treatment of patients with DSP or LOP by focusing on D2 density.