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While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.

Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case–control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.

It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06–1.45, p

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., Plasma levels of MMP‐9 were significantly higher in patients with schizophrenia and significant negative association between plasma MMP‐9 levels and cognitive performance was observed in controls and patients with schizophrenia.

Objective: The objective of the present study was to investigate the feasibility of guided internet cognitive behavioral therapy (ICBT) for anorexia nervosa. Methods: We conducted a prospective single-arm study between January 2020 and March 2021. The intervention was built using videos, web programs, and chat tools. The intervention program was largely based on metacognitive training. Participants performed the self-help program once a week for 12 consecutive weeks. The primary outcome was the global Eating Disorder Examination Questionnaire (EDE-Q) score. Secondary outcomes included clinical symptoms of eating disorders, metacognitive function, body mass index, depression, and generalized anxiety. The main statistical analysis examined whether the EDE-Q score and other outcomes at the end of the intervention differed from the baseline. Results: Fourteen participants underwent the trial treatment, and 13 completed the intervention. There was a significant reduction in the global EDE-Q score from 3.48 (SD = 1.4) to 2.54 (SD = 1.5, p = 0.02, Cohens d = 0.75) from baseline to post-intervention. Some EDE-Q subscales and body checking questionnaire scale demonstrated statistically significant improvements, with moderate to large effect sizes. Although there was no significant improvement in body mass index, metacognitive function, or depressive symptoms, there was a significant improvement in the severity of generalized anxiety (M = -4.0, p = 0.01, Cohens d = 0.95). No adverse events were observed. Discussion: Our findings suggest that guided ICBT for anorexia nervosa is well accepted by female patients and practical as a telemedicine approach that improves symptoms. In the future, tightly controlled randomized controlled trials should be conducted for efficacy verification. Funding Agencies|Japan Society for the Promotion of Science (JSPS) KAKENHIMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI) [18K17313, 19J00227]

BackgroundsThe treatment of mentally disordered offenders is an issue in forensic mental health. In most countries, police officers working in the community are the first to deal with patients at risk of harming themselves or others. However, their perceptions and opinions regarding forensic mental health have not been adequately investigated in Japan.MethodsWe conducted a national survey to gather police officers' views regarding legislation on mentally disordered people and inter-organizational collaboration.ResultsA total of 241 police officers participated in this study. Many participants were aware of the mental health care scheme in their daily work. Contrastingly, many participants complained about the public health center and psychiatrists. They seem to have emerged partially from the differences in each organization's structure, lack of resources, and communication gaps. Many participants felt a lack of opportunity to learn about psychiatry.ConclusionBetter collaborative care for mentally disordered people requires mutual relationships among the police, public health centers, and psychiatrists with a deeper understanding of community mental health.

Background The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS. Methods Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions. Results The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats. Conclusions These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted.

Safe and efficient methods for introducing clozapine to patients with treatment-resistant schizophrenia (TRS) are needed. We investigated risk factors for clozapine discontinuation in the early phase of its introduction.We conducted a nested case-control study at 14 psychiatric hospitals in Chiba, Japan. Data from pre-registered TRS patients were collected at 7 time points within 12 weeks before and after the start of clozapine introduction. We examined the demographic data, prior and concomitant psychotropic drugs, strategies for switching from prior antipsychotics, and blood test and Global Assessment of Function results. The Clinical Global Impression-Severity Scale was retrospectively scored at 12 weeks before and after clozapine introduction.Of 228 patients, clozapine treatment was continued in 213 (93.4 %) and discontinued in 15 (6.6 %) patients within 12 weeks. Clinical symptoms were improved to mild symptoms with a response rate of 14.9 %. Prior antipsychotics and concomitant psychotropic drugs except for mood stabilizers were significantly decreased. Histories of smoking (OR = 3.32, 95 %CI: 1.11-9.93) and antipsychotic treatment at chlorpromazine-equivalent doses1200 mg within the past 5 years (OR = 3.93, 95 %CI: 1.24-12.50), but not antipsychotic switching strategy, were associated with clozapine discontinuation. Eosinophilia was the most frequent reason for discontinuation (n = 3, 20 %) and was associated with concomitant valproate at 4 weeks after the introduction.Clozapine is an effective option for TRS patients (especially those treated with higher doses of prior antipsychotics) in Japan. Clinicians should be cautious about concomitant valproate in the early phase of clozapine introduction due to a high risk of eosinophilia.

Self-medication using over-the-counter (OTC) drugs is an option for the autonomous treatment of several health problems. However, the use of OTC drugs to treat psychiatric conditions remains controversial. To clarify opinions regarding the use of OTC drugs to treat psychiatric problems, we conducted an anonymous online survey of 3000 people in Japan. Participants were stratified into three groups according to their history of mental health problems. Few participants had engaged in self-medication using OTC drugs for psychiatric symptoms, with the exception of insomnia. Participants who had used OTC drugs reported feeling less satisfied with their experience compared with those who had consulted a specialist. Participants who had used sleeping pills were likely to hold relatively positive opinions regarding the use of OTC psychiatric drugs. In conclusion, the need for self-medication of psychiatric symptoms appears to be limited. Education and further research may be necessary to promote self-medication for proper treatment of psychiatric conditions in Japan.

Additional file 1. This file is the whole content of the questionnaire.

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.

Background Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats. Methods Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions. Results In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/β and an increase in the pGSK-3β/GSK-3β ratio, whereas AKT was not changed. Conclusions Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS.

Objective: 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. Results: 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.

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.

It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06-1.45, p 0.001) for rs4680, 1.73 (95% CI 1.47-2.02, p 0.0001) for rs1800497, and 1.79 (95% CI 1.35-2.36, p 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (p 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59-2.19, p 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.

Background: The novel corona virus infection (COVID-19) has immediately become a pandemic. Identifying characteristics of possible “super spreaders,” who are assumed to be a dominant cause of rapid transmission, will help in designing proper prevention strategies. Methods: We conducted a nation-wide online survey to investigate the relationship of understanding and anxiety levels about COVID-19 to possible risk behaviors for spreading the virus in Japan. In total, 4,000 citizens responded to our questionnaire during March 27 and 28, 2020. The questionnaire included several questions covering the level of fear and anxiety about COVID-19, infection preventive behaviors, access to media, level of trust in information about the virus, as well as participants’ demographic characteristics. Findings: In total, 13·7% of participants reported that they have a very low understanding of COVID-19. This study defined those participants as “indifferent individuals.” In addition, 10·6% and 12·2% of them indicated that they have no anxiety of being infected and transmission to others, respectively. We also found that 11·2% showed no worry about symptomatic aggravation, and 8·5% had no concern about spreading the infection. Indifferent individuals were less likely to access information sources than others, and do not trust the information they obtained about the virus. They were less anxious about their own health, and less likely to engage in precautionary behaviors (e.g., washing hands and avoiding crowded spaces) than other participants. Interpretation: The present study suggests it is highly important to educate those who have no concerns about COVID-19, and help them to stop their risk behaviors in order to prevent and control this viral pandemic. Funding Statement: This study was funded by a management grant provided by the Ministry of Education, Culture, Sport, Science and Technology to Chiba University Graduate School of Medicine. Declaration of Interests: The authors declare no conflict of interests regarding this study. Ethics Approval Statement: This study protocol was approved by the Ethics Committee of Chiba University Graduate School of Medicine and the Ethics Committee of the International University of Health and Welfare before implementation. Participants were informed that their participation was voluntary.

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.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

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. 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. 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. 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.

BackgroundGenetic association studies of schizophrenia may be confounded by the pathological heterogeneity and multifactorial nature of this disease. We demonstrated previously that combinations of the three functional single nucleotide polymorphisms (SNPs) rs10770141 of tyrosine hydroxylase (TH) gene, rs4680 of catechol-O-methyltransferase (COMT) gene, and rs1800497 of dopamine D2 receptor (DRD2) gene may be associated with schizophrenia onset, and we tested those associations herein. Methods: We conducted a secondary study of 2,542 individuals in age- and sex-matched case-control populations. The schizophrenia diagnosis was based on the DSM-IV. To reduce the influence of confounders (age and sex), we performed a propensity score matching analysis. Genotyping and associative analyses of rs10770141, rs4680, and rs1800497 with schizophrenia were performed. Results: We analyzed 1,271 schizophrenics (male/female: 574/698; age 47.4±13.9 years) and 1,271 matched controls (male/female: 603/669; age 46.5±13.4 years). The estimated odds ratios (ORs) were 1.245 (p

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.

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.

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., Highlights ● The lack of knowledge about COVID-19 is the core cognitive trait of potential super spreaders who occupy more than 10% of citizens. ● Super spreaders may be in a vicious circle of cognitive indifference, lack of exact information, and recurrent risky behaviors. ● To stop the deterioration of pandemic of COVID-19, we should give proper knowledge to indifferent individuals with any means.

Summary ParagraphSchizophrenia is a highly hereditary mental disease1 related to abnormal dopaminergic activities.2,3 To elucidate the mechanisms underlying schizophrenia’s development, genomic studies have sought to identify the pathogenic genetic polymorphisms. Large-scale genome-wide association studies (GWAS) have reported potential candidate loci that contribute to schizophrenia’s development.4,5 The risk genetic profiles are not yet established. Here we show that the combination of three functional single nucleotide polymorphisms (SNPs) related to the key factors of dopaminergic signaling can be used to predict the risk of schizophrenia’s development, though none of the SNPs is known to be associated by itself. These functional SNPs were reported to demonstrate directional influences in their parent gene activity, perhaps characterizing the integrated properties of dopaminergic signaling. Interestingly, the risk combination presented here included the major genotype as well as the minor polymorphisms, suggesting a possible association of unaffected activities of some dopamine-related genes with the disease development. The phenotype speculated based on the allelic status seemed consistent with the conventional pathophysiological hypotheses, although recently developed predictive methods, such as the polygenic risk score, could miss this potent pathogenic role of carrying a normal genotype by evaluating only minor polymorphisms. Our results demonstrate the presence of a subtype in schizophrenia with the favored genetic background related to dopamine signaling. Our findings indicate the possibility that the combinations could characterize integrated biological functions (including neurotransmission) and therefore identify individuals with a disease risk. The biological microenvironment indicated by the functional SNPs could bring an insight to elucidate the pathogenic mechanisms of developing schizophrenia. Furthermore, we believe that our approach will contribute to the development of innovative means to predict disease risks even for other multi-factorial diseases and then, the following preventive medicine.

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.

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. Electronic supplementary material The online version of this article (10.1186/s13030-018-0125-0) contains supplementary material, which is available to authorized users.

Table S1. Comparison between the patients who were evaluated for psychiatric assessment (the evaluable group) and those who could not be assessed (the unevaluable group). (DOCX 18Â kb)

Figure S1. Representative images of a three-dimensional volume of interest measurement (a) and color mapped image (b) of glucose metabolism measured via 18F-fluorodeoxyglucose positron emission tomography/computed tomography. (PPTX 380Â kb)

Figure S2. All available 18F-fluorodeoxyglucose positron emission tomography/computed tomography images for the 14 patients who had severe traumatic brain injury with or without a behavioral disorder. (PPTX 885Â kb)

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.

Pharmacotherapies for the behavioural and psychological symptoms of dementia are limited; novel agents for the symptoms are still needed. Herein, we report the case of an 80-year-old male patient with Alzheimer's disease whose severe agitation, insomnia and sexual delusions were successfully treated with a traditional natural Japanese (Kampo) medicine, keishi-ka-ryukotsu-borei-to. We found that administrating keishi-ka-ryukotsu-borei-to increased his serum luteinizing hormone level, which could be inversely associated with his behavioural and psychological symptoms. This report suggests that keishi-ka-ryukotsu-borei-to is a possible alternative treatment for the behavioural and psychological symptoms of dementia, especially sexual delusions.

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. 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 ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. 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

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.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.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.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.

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 < 0.0001). Response rates were 85.7 and 10.0% for CBT + UC and UC alone, respectively (p < 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.

Background: As the proportion of teens in the onset ages has increased, it has become important to detect eating disorder (ED) students early in school and clarify the way of support. Though epidemiological surveys of Yogo teachers have been conducted to inquire the number of ED students, none of these were based on DSM-5. Thus, we conducted a wide area survey in Japan for proposing a better framework of support for Yogo teachers in the early detection/support of ED students. 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 1886 responses were obtained. Based on the results, the encounter rates (the proportions of Yogo teachers who had met ED students) were calculated, and factors affecting them were examined by logistic regression analysis. Results: The order of the encounter rates of the ED type was Anorexia Nervosa (AN)>Bulimia Nervosa (BN)>Avoidant/Restrictive Food Intake Disorder (ARFID)>Binge Eating Disorder (BED)>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, BN knowledge for BN, location, school type, experience years, BED knowledge for BED, location, experience years, ARFID knowledge for ARFID and school type, experience years, Others knowledge for Others. Conclusions: Since the encounter rate of AN was highest, providing support for AN would be effective. Moreover, a factor affecting the rate of all ED types was the ED knowledge. Senior high schools had the highest rates for AN, BN and BED, and special needs schools had the highest for others. These findings imply that for detecting/supporting ED students early, it is necessary to offer knowledge of the corresponding ED type to Yogo teachers at the corresponding school type.

Little is known about the association between polyunsaturated fatty acids (PUFAs) and eating-related patho- physiology in anorexia nervosa (AN). The aim of this study was to determine whether nutritional treatment with enteral formula, rich in PUFAs, affects (1) the concentrations of PUFA and brain-derived neurotrophic factor (BDNF) in serum, and (2) the depressive symptoms and eating-related pathophysiology in patients with AN. Thirteen patients with AN par- ticipated in this study. Serum PUFA and BDNF concentrations were measured before and after receiving the enteral for- mula, and eating-related psychopathology and depressive symptomatology were assessed using the eating disorder inven- tory-2 (EDI-2) and the Hamilton Depression Rating Scale (HDRS), respectively. Body mass index (BMI) and HDRS scores showed significant improvement after treatment. Patients receiving the nutritional treatment, enteral formula with enriched PUFAs, favorably adhered to the treatment, and showed significant improvements in BMI and depressive symp- toms. Randomized controlled studies are required to further examine the effectiveness of PUFAs in AN.

Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.

Background: Brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of ma- jor depressive disorder (MDD). Several meta-analyses have shown decreased serum levels of BDNF in adult patients with MDD, but there has been no report on the serum levels of BDNF in pediatric patients with depression. In this study, we investigated whether serum levels of BDNF are altered in pediatric patients with depression. Methods: We measured serum BDNF levels in the following four groups: male pediatric patients with depression (n = 13), female pediatric patients with depression (n = 17), and age-matched normal control subjects (n = 10 for Male, n=12 for Female). Patients were evaluated using the Children's Depression Rating Scale Revised (CDRS-R). Serum levels of BDNF were measured with the sandwich ELISA method. Results: Serum levels (6.97 ± 3.69 ng/mL (mean ± SD)) of BDNF in male pediatric patients with depression were signifi- cantly (p=0.019) lower than those (10.67 ± 3.11 ng/mL) in the male control group. However, there was no difference be- tween the female pediatric patients with depression (9.29 ± 4.61 ng/mL) and the female control group (10.21 ± 4.79 ng/mL). Furthermore, there was no correlation between serum levels of BDNF and CDRS-R scores in the pediatric pa- tients with depression. Interestingly, there was a significant negative correlation (r = -0.683, p=0.010) between the serum BDNF levels and the duration of illness in male, but not female, pediatric patients with depression. Conclusions: This study suggests that low BDNF levels may play a role in the pathophysiology of male pediatric patients with depression.

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 naive DRD2, might indicate vulnerability to development of Ai-DSP. However, further studies are needed to validate the present results.

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.

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 (MDD).This study employed a cross-sectional design. We recruited 78 outpatients consisting of 31 TRD patients, 31 remitted MDD patients, and 16 mildly symptomatic MDD 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 (HDRS).The mean [±SD] score of the IES-R in patients with TRD (46.7 [15.1]) was significantly higher than in remitted (10.3 [9.9], p0.001) or mildly symptomatic (31.3 [7.7], p0.001) patients with MDD. The HDRS scores showed significant correlations with those of the IES-R among all patients (r=0.811).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 due to the cross-sectional design.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.

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.

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.

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.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 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]) (P0.001), 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 or without 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.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.

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.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 p0.0001) outlined by previous GWAS in order to identify possible molecular mechanisms involved in SSRI effect.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.

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.