Gaze behaviors during free viewing revealed differences in visual salience processing across four major psychiatric disorders: a mega-analysis study of 1012 individuals.

Aberrant salience processing has been proposed as a pathophysiological mechanism underlying psychiatric symptoms in patients with schizophrenia. The gaze trajectories of individuals with schizophrenia have been reported to be abnormal when viewing an image, suggesting anomalous visual salience as one possible pathophysiological mechanism associated with psychiatric diseases. This study was designed to determine whether visual salience is affected in individuals with schizophrenia, and whether this abnormality is unique to patients with schizophrenia. We examined the gaze behaviors of 1012 participants recruited from seven institutes (550 healthy individuals and 238, 41, 50 and 133 individuals with schizophrenia, bipolar disorder, major depressive disorder and autism spectrum disorder, respectively) when they looked at stationary images as they liked, i.e., free-viewing condition. We used an established computational model of salience maps derived from low-level visual features to measure the degree to which the gaze trajectories of individuals were guided by visual salience. The analysis revealed that the saliency at the gaze of individuals with schizophrenia were higher than healthy individuals, suggesting that patients' gazes were guided more by low-level image salience. Among the low-level image features, orientation salience was most affected. Furthermore, a general linear model analysis of the data for the four psychiatric disorders revealed a significant effect of disease. This abnormal salience processing depended on the disease and was strongest in patients with schizophrenia, followed by patients with bipolar disorder, major depressive disorder, and autism spectrum disorder, suggesting a link between abnormalities in salience processing and strength/frequency for psychosis of these disorders.

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Neuropathological substrate of incident dementia in older patients with schizophrenia: A clinicopathological study.

AIM: Clinical studies reported that patients with schizophrenia are at a higher risk of developing dementia than people without schizophrenia. However, early neuropathological studies have shown that the incidence of Alzheimer's disease (AD) in schizophrenia patients does not differ from that in controls. These inconsistent results may be attributable to the inclusion of non-AD dementia, but there have been few clinicopathological studies in older patients with schizophrenia based on the current neuropathological classification. This study aimed to investigate the neuropathological basis of incident dementia in older patients with schizophrenia. METHODS: We systematically examined 32 brains of old patients with schizophrenia using standardized pathological methods. The severity of dementia-related neuropathologies was analyzed using standardized semiquantitative assessments. After excluding patients who fulfilled the neuropathological criteria, clinicopathological variables were compared between patients with and without incident dementia to identify potential differences. RESULTS: Seven patients fulfilled the pathological criteria for AD (n = 3), argyrophilic grain disease (AGD) (n = 2), dementia with Lewy bodies (n = 1), and AGD/progressive supranuclear palsy (n = 1). Among 25 patients for whom a neuropathological diagnosis was not obtained, 10 had dementia, but the clinicopathological findings did not differ from the remaining 15 patients without dementia. CONCLUSION: Two types of older schizophrenia patient present dementia: patients with co-existing neurodegenerative disease and patients who do not meet pathological criteria based on the current classification. To understand the neurobiological aspects of incident dementia in older patients with schizophrenia, further clinicopathological studies are needed that do not simply analyze incident dementia as a comorbidity of conventional dementia-related neuropathologies.

Identification of risk loci for postpartum depression in a genome-wide association study.

AIM: Genome-wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD-associated loci. METHODS: The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders. RESULTS: A meta-analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10-8) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over-represented in categories including long-term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling. CONCLUSION: The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis.

Anxiety, depression and quality of life in patients with head and neck cancer undergoing laryngectomy: A long-term prospective evaluation.

BACKGROUND: This study aimed to assess anxiety, depression and quality of life (QoL) in patients with head and neck cancer undergoing laryngectomy using comprehensive self-reported questionnaires for a period of up to 5 years. METHODS: This prospective observational study enrolled 150 consecutive patients with locally advanced head and neck cancer who underwent laryngectomy at Nagoya University Hospital between 2007 and 2020. Anxiety, depression and QoL were assessed at baseline (preoperative) and at 3, 6, 12, 24, 36, 48 and 60 months after surgery using two brief self-reported questionnaires, such as the eight-item Short Form Health Survey (SF-8) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: The surgical procedures were total laryngectomy, pharyngo-laryngectomy and pharyngo-laryngo-oesophagectomy in 97 (65%), 41 (27%) and 12 (8%) patients, respectively. All eight items of the SF-8 were significantly worse than those of the normal population at baseline and at 3 months after surgery. However, general health, vitality, mental health and bodily pain improved to normal levels within 1 year after surgery and were maintained for 5 years. In this study, 35% of patients were categorised as potential cases of depression, and 35% were potential cases of anxiety. During the follow-up period, the proportion of patients with anxiety gradually decreased after surgery. Further analysis revealed that the SF-8 and HADS scores and trends in 89 patients without tumour recurrence were similar to those in the total enrolled 150 patients. CONCLUSION: Anxiety, depression and QoL in laryngectomised patients improved at 1 year after surgery and were maintained for up to 5 years. WHAT THIS PAPER ADDS: What is already known on the subject Laryngectomy is associated with prolonged functional and psychological effects and has a major impact on patient quality of life (QoL). Several prospective studies evaluating the QoL in laryngectomised patients have been reported, in which significant deterioration in social functioning was found even 1 year after surgery. What this paper adds to existing knowledge One year is not a sufficient period for laryngectomised patients to return to normal life and spend their time in a social community. A recent review showed that most studies on QoL in laryngectomised patients were conducted under 1 year after the procedure, and there were not enough studies of sufficient quality. This is the first long-term prospective observational study of Japanese patients with head and neck cancer who underwent laryngectomy up to 5 years after surgery. What are the potential or actual clinical implications of this work? Our long-term observational study showed that the scores for anxiety, depression and QoL in laryngectomised patients improved at 1 year after surgery and were maintained for up to 5 years. Clinicians should recognize the importance of psychosocial risk factors in their QoL and multidisciplinary management, including social and psychological support, is essential for long-term laryngectomised survivors.

Astrotactin 2 (ASTN2) regulates emotional and cognitive functions by affecting neuronal morphogenesis and monoaminergic systems.

Astrotactin2 (ASTN2) regulates neuronal migration and synaptic strength through the trafficking and degradation of surface proteins. Deletion of ASTN2 in copy number variants has been identified in patients with schizophrenia, bipolar disorder, and autism spectrum disorder in copy number variant (CNV) analysis. Disruption of ASTN2 is a risk factor for these neurodevelopmental disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. However, the importance of ASTN2 in physiological functions remains poorly understood. To elucidate the physiological functions of ASTN2, we investigated whether deficiency of ASTN2 affects cognitive and/or emotional behaviors and neurotransmissions using ASTN2-deficient mice. Astn2 knockout (KO) mice produced by CRISPR/Cas9 technique showed no obvious differences in physical characteristics and circadian rhythm. Astn2 KO mice showed increased exploratory activity in a novel environment, social behavior and impulsivity, or decreased despair-, anxiety-like behaviors and exploratory preference for the novel object. Some behavioral abnormalities, such as increased exploratory activity and impulsivity, or decreased exploratory preference were specifically attenuated by risperidone, but not by haloperidol. While, the both drugs did not affect any emotion-related behavioral abnormalities in Astn2 KO mice. Dopamine contents were decreased in the striatum, and serotonin or dopamine turnover were increased in the striatum, nucleus accumbens, and amygdala of Astn2 KO mice. In morphological analyses, thinning of neural cell layers in the hippocampus, reduction of neural cell bodies in the prefrontal cortex, and decrease in spine density and PSD95 protein in both tissues were observed in Astn2 KO mice. The present findings suggest that ASTN2 deficiency develops some emotional or cognitive impairments related to monoaminergic dysfunctions and abnormal neuronal morphogenesis with shrinkage of neuronal soma. ASTN2 protein may contribute to the pathogenic mechanism and symptom onset of mental disorders.

The genetic architecture of schizophrenia: review of large-scale genetic studies.

Schizophrenia is a complex and often chronic psychiatric disorder with high heritability. Diagnosis of schizophrenia is still made clinically based on psychiatric symptoms; no diagnostic tests or biomarkers are available. Pathophysiology-based diagnostic scheme and treatments are also not available. Elucidation of the pathogenesis is needed for development of pathology-based diagnostics and treatments. In the past few decades, genetic research has made substantial advances in our understanding of the genetic architecture of schizophrenia. Rare copy number variations (CNVs) and rare single-nucleotide variants (SNVs) detected by whole-genome CNV analysis and whole-genome/-exome sequencing analysis have provided the great advances. Common single-nucleotide polymorphisms (SNPs) detected by large-scale genome-wide association studies have also provided important information. Large-scale genetic studies have been revealed that both rare and common genetic variants play crucial roles in this disorder. In this review, we focused on CNVs, SNVs, and SNPs, and discuss the latest research findings on the pathogenesis of schizophrenia based on these genetic variants. Rare variants with large effect sizes can provide mechanistic hypotheses. CRISPR-based genetics approaches and induced pluripotent stem cell technology can facilitate the functional analysis of these variants detected in patients with schizophrenia. Recent advances in long-read sequence technology are expected to detect variants that cannot be detected by short-read sequence technology. Various studies that bring together data from common variant and transcriptomic datasets provide biological insight. These new approaches will provide additional insight into the pathophysiology of schizophrenia and facilitate the development of pathology-based therapeutics.

Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene.

Copy-number variations in the ARHGAP10 gene encoding Rho GTPase-activating protein 10 are associated with schizophrenia. Model mice (Arhgap10 S490P/NHEJ mice) that carry "double-hit" mutations in the Arhgap10 gene mimic the schizophrenia in a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether the activation of RhoA/Rho-kinase signaling due to schizophrenia-associated Arhgap10 mutations causes the phenotypes of these model mice. Here, we investigated the effects of fasudil, a brain permeable Rho-kinase inhibitor, on altered spine density in the medial prefrontal cortex (mPFC) and on methamphetamine-induced cognitive impairment in a touchscreen­based visual discrimination task in Arhgap10 S490P/NHEJ mice. Fasudil (20 mg/kg, intraperitoneal) suppressed the increased phosphorylation of myosin phosphatase-targeting subunit 1, a substrate of Rho-kinase, in the striatum and mPFC of Arhgap10 S490P/NHEJ mice. In addition, daily oral administration of fasudil (20 mg/kg/day) for 7 days ameliorated the reduced spine density of layer 2/3 pyramidal neurons in the mPFC. Moreover, fasudil (3-20 mg/kg, intraperitoneal) rescued the methamphetamine (0.3 mg/kg)-induced cognitive impairment of visual discrimination in Arhgap10 S490P/NHEJ mice. Our results suggest that Rho-kinase plays significant roles in the neuropathological changes in spine morphology and in the vulnerability of cognition to methamphetamine in mice with schizophrenia-associated Arhgap10 mutations.

Rho kinase inhibitors ameliorate cognitive impairment in a male mouse model of methamphetamine-induced schizophrenia.

Schizophrenia (SCZ) is a severe psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits. Current antipsychotic treatment in SCZ improves positive symptoms but has major side effects and little impact on negative symptoms and cognitive impairment. The pathoetiology of SCZ remains unclear, but is known to involve small GTPase signaling. Rho kinase, an effector of small GTPase Rho, is highly expressed in the brain and plays a major role in neurite elongation and neuronal architecture. This study used a touchscreen-based visual discrimination (VD) task to investigate the effects of Rho kinase inhibitors on cognitive impairment in a methamphetamine (METH)-treated male mouse model of SCZ. Systemic injection of the Rho kinase inhibitor fasudil dose-dependently ameliorated METH-induced VD impairment. Fasudil also significantly suppressed the increase in the number of c-Fos-positive cells in the infralimbic medial prefrontal cortex (infralimbic mPFC) and dorsomedial striatum (DMS) following METH treatment. Bilateral microinjections of Y-27632, another Rho kinase inhibitor, into the infralimbic mPFC or DMS significantly ameliorated METH-induced VD impairment. Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the infralimbic mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases. Oral administration of haloperidol and fasudil ameliorated METH-induced VD impairment, while clozapine had little effect. Oral administration of haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. These results suggest that METH activates Rho kinase in the infralimbic mPFC and DMS, which leads to cognitive impairment in male mice. Rho kinase inhibitors ameliorate METH-induced cognitive impairment, perhaps via the cortico-striatal circuit.

Comorbid psychiatric disorders and long-term survival after liver transplantation in transplant facilities with a psychiatric consultation-liaison team: a multicenter retrospective study.

OBJECTIVE: Comorbid psychiatric disorders negatively affect the survival rate of patients with some physical disorders. In liver transplant recipients, various psychiatric disorders have been identified as worsening prognosis. However, little is known about how the presence of any comorbid (overall) disorders affect the survival rate of transplant recipients. In this study, we examined the effect of overall comorbid psychiatric disorders on survival rate in liver transplant recipients. METHODS: A total of 1006 recipients who underwent liver transplantation between September 1997 and July 2017 across eight transplant facilities with a psychiatric consultation-liaison team were identified consecutively. Recipients were categorized into those with comorbid psychiatric disorders and those without comorbid psychiatric disorders. In the comorbid psychiatric disorder group, psychiatric disorder diagnosis and time of diagnosis were investigated retrospectively. RESULTS: Of the 1006 recipients, 294 (29.2%) had comorbid psychiatric disorders. Comorbid psychiatric disorders in the 1006 recipients were insomnia (N = 107, 10.6%), delirium (N = 103, 10.2%), major depressive disorder (N = 41, 4.1%), adjustment disorder (N = 19, 1.9%), anxiety disorder (N = 17, 1.7%), intellectual disability (N = 11, 1.1%), autism spectrum disorder (N = 7, 0.7%), somatic symptom disorder (N = 4, 0.4%) schizophrenia (N = 4, 0.4%), substance use disorder (N = 24, 2.4%) and personality disorder (N = 2, 0.2%). The most common time of psychiatric disorder diagnosis was within the first 3 months after liver transplantation (51.6%). The final mortality in patients with comorbid psychiatric disorder diagnosis during the five periods (pretransplant, transplant to 3 months, months to 1 year, 1 to 3 years, and over 3 years posttransplant) was 16.2%, 18.8%, 39.1%, 28.6%, and 16.2% respectively, and there were no significant differences between the five periods (χ2 = 8.05, df = 4, p = 0.09). Overall comorbid psychiatric disorders were significantly associated with shorter survival time (log-rank test: p = 0.01, hazard ratio: 1.59 [95% confidence interval: 1.14-2.21], survival rate at the endpoint [%]: 62.0 vs. 83.3). However, after adjusting for confounding variables using Cox proportional hazards regression, there was no significant effect of overall comorbid psychiatric disorders on prognosis. CONCLUSION: Comorbid psychiatric disorders did not affect the survival rate of liver transplant recipients in this study.

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial.

BACKGROUND: Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. METHODS: In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups (n = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. DISCUSSION: This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

Comparison of Polysomnography, Single-Channel Electroencephalogram, Fitbit, and Sleep Logs in Patients With Psychiatric Disorders: Cross-Sectional Study.

BACKGROUND: Sleep disturbances are core symptoms of psychiatric disorders. Although various sleep measures have been developed to assess sleep patterns and quality of sleep, the concordance of these measures in patients with psychiatric disorders remains relatively elusive. OBJECTIVE: This study aims to examine the degree of agreement among 3 sleep recording methods and the consistency between subjective and objective sleep measures, with a specific focus on recently developed devices in a population of individuals with psychiatric disorders. METHODS: We analyzed 62 participants for this cross-sectional study, all having data for polysomnography (PSG), Zmachine, Fitbit, and sleep logs. Participants completed questionnaires on their symptoms and estimated sleep duration the morning after the overnight sleep assessment. The interclass correlation coefficients (ICCs) were calculated to evaluate the consistency between sleep parameters obtained from each instrument. Additionally, Bland-Altman plots were used to visually show differences and limits of agreement for sleep parameters measured by PSG, Zmachine, Fitbit, and sleep logs. RESULTS: The findings indicated a moderate agreement between PSG and Zmachine data for total sleep time (ICC=0.46; P<.001), wake after sleep onset (ICC=0.39; P=.002), and sleep efficiency (ICC=0.40; P=.006). In contrast, Fitbit demonstrated notable disagreement with PSG (total sleep time: ICC=0.08; wake after sleep onset: ICC=0.18; sleep efficiency: ICC=0.10) and exhibited particularly large discrepancies from the sleep logs (total sleep time: ICC=-0.01; wake after sleep onset: ICC=0.05; sleep efficiency: ICC=-0.02). Furthermore, subjective and objective concordance among PSG, Zmachine, and sleep logs appeared to be influenced by the severity of the depressive symptoms and obstructive sleep apnea, while these associations were not observed between the Fitbit and other sleep instruments. CONCLUSIONS: Our study results suggest that Fitbit accuracy is reduced in the presence of comorbid clinical symptoms. Although user-friendly, Fitbit has limitations that should be considered when assessing sleep in patients with psychiatric disorders.

Shedding light on latent pathogenesis and pathophysiology of mental disorders: The potential of iPS cell technology.

Mental disorders are considered as one of the major healthcare issues worldwide owing to their significant impact on the quality of life of patients, causing serious social burdens. However, it is hard to examine the living brain-a source of psychiatric symptoms-at the cellular, subcellular, and molecular levels, which poses difficulty in determining the pathogenesis and pathophysiology of mental disorders. Recently, induced pluripotent stem cell (iPSC) technology has been used as a novel tool for research on mental disorders. We believe that the iPSC-based studies will address the limitations of other research approaches, such as human genome, postmortem brain study, brain imaging, and animal model analysis. Notably, studies using integrated iPSC technology with genetic information have provided significant novel findings to date. This review aimed to discuss the history, current trends, potential, and future of iPSC technology in the field of mental disorders. Although iPSC technology has several limitations, this technology can be used in combination with the other approaches to facilitate studies on mental disorders.

Functional connector hubs in the cerebellum.

Accumulating evidence from anatomical and neuroimaging studies suggests that the cerebellum is engaged in a variety of motor and cognitive tasks. Given its various functions, a key question is whether the cerebellum also plays an important role in the brain's integrative functions. Here, we hypothesize the existence of connector regions, also known as connector hubs, where multiple resting state networks converged in the cerebellum. To verify this, we employed a recently developed voxel-level network measure called functional connectivity overlap ratio (FCOR), which could be used to quantify the spatial extent of a region's connection to several large-scale cortical networks. Using resting state functional MRI data from 101 healthy participants, cerebellar FCOR maps were constructed and used to identify the locations of connector hubs in the cerebellum. Results showed that a number of cerebellar regions exhibited strong connectivity with multiple functional networks, verifying our hypothesis. These highly connected regions were located in the posterior cerebellum, especially in lobules VI, VII, and IX, and mainly connected to the core neurocognitive networks such as default mode and executive control networks. Regions associated with the sensorimotor network were also localized in lobule V, VI, and VIII, albeit in small clusters. These cerebellar connector hubs may play an essential role in the processing of information across the core neurocognitive networks.

Prevalence, clinical features, and risk factors of delusions in patients with delirium.

OBJECTIVES: Delirium may be divided into multiple subtypes with different pathological factors. This study aimed to focus on the delirium subtype in which delusions are conspicuous and explore its prevalence, clinical characteristics, and risk factors. METHODS: The subjects were 601 delirium cases referred to the department of psychiatry over 5 years at a general hospital. The Delirium Rating Scale-Revised-98 was used to assess the delusions in patients with delirium, and the features of delusions (delusional form, object, and content) were examined. Multiple regression analysis was applied to determine whether individual factors were associated with the delusions. RESULTS: A total of 78 patients with delirium experienced delusions (13.0%). Most were classified as delusion of reference, such as persecution or poisoning, and 84.3% of patients believed that the persecutors were medical staff members. Older age (p < 0.001), female gender (p < 0.001), and living alone (p < 0.001) were significantly associated with delusions in patients with delirium. CONCLUSIONS: The content of delusions was rooted in the distress caused by the patients' medical situation, and the features and risk factors of the delusions suggested a formal similarity with late paraphrenia and "lack-of-contact paranoia." Psychological interventions that consider the isolation, anxiety, and fear behind delusions may be necessary in the care and treatment of these patients.

A Reactive Metabolite of Clozapine Induces Hematopoietic Toxicity in HL-60 Cells Undergoing Granulocytic Differentiation through Its Effect on Glutathione Metabolism.

Clozapine is an atypical antipsychotic with several advantages over conventional antipsychotics, in addition to its well-known efficacy in treatment-resistant schizophrenia. However, the high risk of agranulocytosis associated with clozapine therapy limits its clinical application. Clozapine bioactivation to an unstable protein-reactive metabolite, identified as a nitrenium intermediate, has been implicated in cytotoxicity toward neutrophils. Clozapine affects myeloid precursor cells rather than neutrophils; however, the impact of its reactive metabolite on myeloid precursor cells undergoing granulocytic differentiation remains unclear. Herein, we used hydrogen peroxide (H2O2) to generate the reactive metabolite and compared reactive metabolite-induced cytotoxicity between HL-60 cells undergoing granulocytic differentiation and differentiated HL-60 cells. In addition, we examined the role of oxidative stress in this type of cytotoxicity. The reactive metabolite of clozapine induced rapid cytotoxicity in HL-60 cells undergoing granulocytic differentiation, but not in differentiated HL-60 cells, with the metabolite exhibiting more potent cytotoxicity than clozapine. No cytotoxicity was observed following incubation with olanzapine, a structural analog of clozapine, even after exposure of the drug to H2O2. The reactive metabolite of clozapine decreased the levels of reduced glutathione, while addition of reduced glutathione attenuated the reactive metabolite-induced cytotoxicity. These findings indicate that glutathione metabolism plays a role in the hematopoietic toxicity induced by the reactive metabolite of clozapine. Oxidative stress may potentially increase susceptibility to the hematopoietic toxicity induced by the reactive metabolite of clozapine.