Live two-way video versus face-to-face treatment for depression, anxiety, and obsessive-compulsive disorder: A 24-week randomized controlled trial.

AIM: Live two-way video, easily accessible from home via smartphones and other devices, is becoming a new way of providing psychiatric treatment. However, lack of evidence for real-world clinical setting effectiveness hampers its approval by medical insurance in some countries. Here, we conducted the first large-scale pragmatic, randomized controlled trial to determine the effectiveness of long-term treatment for multiple psychiatric disorders via two-way video using smartphones and other devices, which are currently the primary means of telecommunication. METHODS: This randomized controlled trial compared two-way video versus face-to-face treatment for depressive disorder, anxiety disorder, and obsessive-compulsive disorder in the subacute/maintenance phase during a 24-week period. Adult patients with the above-mentioned disorders were allocated to either a two-way video group (≥50% video sessions) or a face-to-face group (100% in-person sessions) and received standard treatment covered by public medical insurance. The primary outcome was the 36-Item Short-Form Health Survey Mental Component Summary (SF-36 MCS) score. Secondary outcomes included all-cause discontinuation, working alliance, adverse events, and the severity rating scales for each disorder. RESULTS: A total of 199 patients participated in this study. After 24 weeks of treatment, two-way video treatment was found to be noninferior to face-to-face treatment regarding SF-36 MCS score (48.50 vs 46.68, respectively; p < 0.001). There were no significant differences between the groups regarding most secondary end points, including all-cause discontinuation, treatment efficacy, and satisfaction. CONCLUSION: Two-way video treatment using smartphones and other devices, was noninferior to face-to-face treatment in real-world clinical settings. Modern telemedicine, easily accessible from home, can be used as a form of health care.

Bispectral EEG (BSEEG) Algorithm Captures High Mortality Risk Among 1,077 Patients: Its Relationship to Delirium Motor Subtype.

OBJECTIVE: Delirium is dangerous and a predictor of poor patient outcomes. We have previously reported the utility of the bispectral EEG (BSEEG) with a novel algorithm for the detection of delirium and prediction of patient outcomes including mortality. The present study employed a normalized BSEEG (nBSEEG) score to integrate the previous cohorts to combine their data to investigate the prediction of patient outcomes. We also aimed to test if the BSEEG method can be applicable regardless of age, and independent of delirium motor subtypes. METHODS: We calculated nBSEEG score from raw BSEEG data in each cohort and classified patients into BSEEG-positive and BSEEG-negative groups. We used log-rank test and Cox proportional hazards models to predict 90-day and 1-year outcomes for the BSEEG-positive and -negative groups in all subjects and motor subgroups. RESULTS: A total of 1,077 subjects, the BSEEG-positive group showed significantly higher 90-day (hazard ratio 1.33 [95% CI 1.16-1.52] and 1-year (hazard ratio 1.22 [95% CI 1.06-1.40] mortality rates than the negative group after adjustment for covariates such as age, sex, CCI, and delirium status. Among patients with different motor subtypes of delirium, the hypoactive group showed significantly higher 90-day (hazard ratio 1.41 [95% CI 1.12-1.76] and 1-year mortality rates (hazard ratio 1.32 [95% CI 1.05-1.67], which remained significant after adjustment for the same covariates. CONCLUSION: We found that the BSEEG method is capable of capturing patients at high mortality risk.

A reciprocal inhibition model of alternations between under-/overemotional modulatory states in patients with PTSD.

Patients with posttraumatic stress disorder (PTSD) appear to manifest two opposing tendencies in their attentional biases and symptoms. However, whether common neural mechanisms account for their opposing attentional biases and symptoms remains unknown. We here propose a model in which reciprocal inhibition between the amygdala and ventromedial prefrontal cortex (vmPFC) predicts synchronized alternations between emotional under- and overmodulatory states at the neural, behavioral, and symptom levels within the same patients. This reciprocal inhibition model predicts that when the amygdala is dominant, patients enter an emotional undermodulatory state where they show attentional bias toward threat and manifest re-experiencing symptoms. In contrast, when the vmPFC is dominant, patients are predicted to enter an emotional overmodulatory state where they show attentional bias away from threat and avoidance symptoms. To test the model, we performed a behavioral meta-analysis (total N = 491), analyses of own behavioral study (N = 20), and a neuroimaging meta-analysis (total N = 316). Supporting the model, we found the distributions of behavioral attentional measurements to be bimodal, suggesting alternations between the states within patients. Moreover, attentional bias toward threat was related to re-experiencing symptoms, whereas attentional bias away from threat was related with avoidance symptoms. We also found that the increase and decrease of activity in the left amygdala activity was related with re-experiencing and avoidance symptoms, respectively. Our model may help elucidate the neural mechanisms differentiating nondissociative and dissociative subtypes of PTSD, which usually show differential emotional modulatory levels. It may thus provide a new venue for therapies targeting each subtype.

Polygenic risk score as clinical utility in psychiatry: a clinical viewpoint.

Genome-wide association studies (GWASs) have detected many susceptible variants for common diseases, including psychiatric disorders. However, because of the small effect size of each variant, clinical utility that aims for risk prediction and/or diagnostic assistance based on the individual "variants" is difficult to use. Therefore, to improve the statistical power, polygenic risk score (PRS) has been established and applied in the GWAS as a robust analytic tool. Although PRS has potential predictive ability, because of its current "insufficient" discriminative power at the individual level for clinical use, it remains limited solely in the research area, specifically in the psychiatric field. For a better understanding of the PRS, in this review, we (1) introduce the clinical features of psychiatric disorders, (2) summarize the recent GWAS/PRS findings in the psychiatric disorders, (3) evaluate the problems of PRS, and (4) propose its possible utility to apply PRS into the psychiatric clinical setting.

ATP and repetitive electric stimulation increases leukemia inhibitory factor expression in astrocytes: A potential role for astrocytes in the action mechanism of electroconvulsive therapy.

AIM: Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes. METHODS: Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA. RESULTS: ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it. CONCLUSION: P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.

Clinical application of DEX/CRH test and multi-channel NIRS in patients with depression.

BACKGROUND: To reduce the number of patients with depression, biomarkers for clarifying psychiatric disorders are warranted. Numerous candidates have been proposed; however, near-infrared spectroscopy (NIRS) with multi-channel probes and a dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are still surviving for practical demand. Thirty-one outpatients with depressed moods were analyzed using both biological tests. RESULTS: The non-suppressors, as indicated by the DEX/CRH test, exhibited a high severity on the Hamilton Depression Scale and severe anxiety on the State Trait Anxiety Scale. In addition, a unique response was identified via NIRS in the same group suggested by the DEX/CRH assessment. CONCLUSIONS: The results obtained from these biological tests did not fit well with the category defined by operative diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders or The International Classification of Diseases. Thus, it is critical that the utility evaluations of candidate biomarkers not be assessed by comparisons with the categorized criteria for a specific psychiatric disorder. Trial registration UMIN000013214, Registered 21 February 2014.

Comparative analysis of autistic traits and behavioral disorders in Prader-Willi syndrome and Asperger disorder.

Prader-Willi syndrome (PWS) is a neuro-genetic disorder caused by the absence/loss of expression of one or more paternally expressed genes on chromosome 15 (q11-13). In this study, a comparative analysis of intelligence level and autistic traits was conducted between children with PWS (n = 30; 18 males, 12 females; age = 10.6 ± 2.8 years) and those with Asperger disorder (AD; n = 31; 24 males, 7 females; age = 10.5 ± 3.1 years). The children were compared by age group: lower elementary school age (6-8 years), upper elementary school age (9-12 years), and middle school age (13-15 years). As results, the intelligence levels of children with PWS were significantly lower than those with AD across all age groups. Autistic traits, assessed using the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), revealed that among elementary school age children, those with PWS had less prominent autistic traits than those with AD, however, among middle school age children, those with PWS and AD showed similar prominence. An analysis of the PARS subscale scores by age group showed that while the profiles of autistic traits for children with PWS differed from those of children with AD at elementary school age, the profiles showed no significant differences between the groups at middle school age. The findings suggest that autistic traits in PWS become gradually more prominent with increasing of age and that these autistic traits differ in their fundamental nature from those observed in AD.

Microarray Analysis of Human Blood During Electroconvulsive Therapy.

INTRODUCTION: Electroconvulsive therapy (ECT) is currently regarded as a significant treatment option for intractable psychiatric disorders, such as catatonic schizophrenia or treatment-resistant depression; however, the underlying molecular mechanism for its therapeutic effect remains obscure. METHODS: Employing microarray analysis (Human Genome U133 Plus 2.0 Array; Affymetrix, United States) of cDNA derived from the peripheral blood of patients with catatonic schizophrenia (n = 5), we detected a significant change in 145 genes (0.68%) before and after modified ECT (mECT). Moreover, we performed quantitative polymerase chain reaction validation of genes that had previously been suggested to be functionally related to schizophrenia. RESULTS: Of 4 genes examined (AKT3, TCF7, PPP3R1, and GADD45B), only TCF7 was increased during the mECT procedure (P = 0.0025). DISCUSSION: This study describes the first attempt to uncover the molecular mechanism of mECT using a microarray assay of mRNA derived from peripheral blood, and our results suggest that the TCF family may play a role in the functional mechanism of mECT.

[The Schizophrenia Spectrum and Other Psychotic Disorders in DSM-5].

Characteristic changes to schizophrenia in DSM-5 are the downgrading of Schneiderian first-rank symptoms and the elimination of subtypes in schizophrenia. Since dimensional evaluation was officially suspended, schizophrenia with a flat face has been described in DSM-5. Recent genomic research, especially involving CNV analysis, has revealed that the categories in DSM are not based on biological information. Because "schizophrenia" was initially just a temporary diagnosis before the clarification of its biological basis, it will be divided when a clear etiology or causal genetic information is found in the future. Meanwhile, we have to follow its changes in a clinical setting due to the lack of alternatives to DSM. Since the practical "perspective" on the disorder is different from research to clarify its etiology, it is impossible, to set one diagnostic criterion to satisfy the requirements from these two perspectives. It will be necessary to use the RDoC in future research for effective categorization.

Beyond lecanemab: Examining Phase III potential in Alzheimer's therapeutics.

This review focuses on the development of therapeutic interventions for Alzheimer's dementia. While established treatments targeted acetylcholine and NMDA receptors, there is a growing demand for innovative therapies as the aging population increases. The paper highlights the US Food and Drug Administration's approval of aducanumab (Aduhelm) and lecanemab (Leqembi), emphasizing the developmental status of new treatments. Specifically, it covers seven principal drugs in Phase III trials, detailing their mechanisms of action, clinical trial specifics in the United States and Japan, and the current status of regulatory applications. The review focuses on amyloid removal (donanemab), tau protein mitigation (E2814), drug repositioning (Semaglutide, GV1001), and disease-modifying small molecules (fosgonimeton, hydralazine, masitinib). However, Gantenerumab and Solanezumab, unsuccessful in Phase III, are not covered. While the future approval status remains uncertain, we hope these drugs will offer beneficial therapeutic effects for potential dementia patients.

Effects of intensity, frequency, and time window of exercise on sleep quality among community-dwelling adults aged 65-86 years.

BACKGROUND: Although the effects of exercise training (ET) on sleep problem have been reported, the effects according to the components of exercise, including intensity, frequency, and time window, are unknown. Thus, in this study, we aimed to assess the effects of ET on sleep quality in community-dwelling older adults with sleep problems. METHODS: We evaluated individuals aged ≥65 years whose Pittsburgh sleep quality index was >5 points at baseline. The participants were allocated to either the control group or the ET group and underwent interval walking training (IWT) for 5 months. Information regarding intensity, frequency, and time window of ET were obtained using a waist-worn accelerometer. RESULTS: Overall, 63 participants (24 men [mean ± standard deviation age: 75.1 ± 4.6 years] and 39 women [74.7 ± 5.2 years]) and 65 participants (24 men [75.2 ± 4.0 years] and 41 women [73.6 ± 4.2 years]) were included in the ET and control groups, respectively. The change in Pittsburgh sleep quality index was not significantly different between the two groups for both sexes. In the ET group, women who exercised 3-8 h before bedtime, men who did ET > 8 h before bedtime and more than 1 h after waking up, and men who did ET ≥ 5.05 days/week experienced significant improvements compared to the baseline. CONCLUSIONS: IWT does not significantly improve sleep quality. To obtain improvements in sleep quality, it might be necessary to consider the time window of performing ET for both sexes and ET frequency for men.

Real-world outcome of rTMS treatment for depression within the Japanese public health insurance system: Registry data from Kansai TMS network.

This study registered consecutive cases to elucidate the efficacy of rTMS treatment for depression within the Japanese public health insurance system. Of the 102 patients with depression who received rTMS over the left dorsolateral prefrontal cortex, 44 (43.1 %) patients reached remission and 14 (13.7 %) patients did not reach remission but responded to treatment. No serious adverse events occurred. Low baseline HAMD-17 score was associated with remission after rTMS treatment. Favorable outcomes of rTMS treatment were shown in this cohort within the Japanese public insurance system. Our results provide insights into rTMS treatment for depression in real-world clinical setting.

The Genome-wide DNA methylation changes in gastrointestinal surgery patients with and without postoperative delirium: Evidence of immune process in its pathophysiology.

AIM: The pathophysiological mechanisms of postoperative delirium (POD) are still unclear, and there is no reliable biomarker to distinguish between those with and without POD. Our aim was to discover DNAm markers associated with POD in blood collected from patients before and after gastrointestinal surgery. METHOD: We collected blood samples from 16 patients including 7 POD patients at three timepoints; before surgery (pre), the first and third postoperative days (day1 and day3). We measured differences in DNA methylation between POD and control groups between pre and day1 as well as between pre and day3 using the Illumina EPIC array method. Besides, enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also performed after excluding influence of common factors related to surgery and anesthesia. RESULT: The results showed that pre and day1 comparisons showed that immune and inflammatory signals such as 'T-cell activation' were significantly different, consistent with our previous studies with non-Hispanic White subjects. In contrast, we found that these signals were not significant any more when pre was compared with day3. CONCLUSION: These results provide strong evidence for the involvement of inflammatory and immune-related epigenetic signals in the pathogenesis of delirium, including POD, regardless of ethnic background. These findings also suggest that DNAm, which is involved in inflammation and immunity, is dynamically altered in patients with POD. In summary, the present results indicate that these signals may serve as a new diagnostic tool for POD.

Epigenetic signals associated with delirium replicated across four independent cohorts.

Delirium is risky and indicates poor outcomes for patients. Therefore, it is crucial to create an effective delirium detection method. However, the epigenetic pathophysiology of delirium remains largely unknown. We aimed to discover reliable and replicable epigenetic (DNA methylation: DNAm) markers that are associated with delirium including post-operative delirium (POD) in blood obtained from patients among four independent cohorts. Blood DNA from four independent cohorts (two inpatient cohorts and two surgery cohorts; 16 to 88 patients each) were analyzed using the Illumina EPIC array platform for genome-wide DNAm analysis. We examined DNAm differences in blood between patients with and without delirium including POD. When we compared top CpG sites previously identified from the initial inpatient cohort with three additional cohorts (one inpatient and two surgery cohorts), 11 of the top 13 CpG sites showed statistically significant differences in DNAm values between the delirium group and non-delirium group in the same directions as found in the initial cohort. This study demonstrated the potential value of epigenetic biomarkers as future diagnostic tools. Furthermore, our findings provide additional evidence of the potential role of epigenetics in the pathophysiology of delirium including POD.

Genome-wide association study of atypical psychosis.

Atypical psychosis with a periodic course of exacerbation and features of major psychiatric disorders [schizophrenia (SZ) and bipolar disorder (BD)] has a long history in clinical psychiatry in Japan. Based upon the new criteria of atypical psychosis, a Genome-Wide Association Study (GWAS) was conducted to identify the risk gene or variants. The relationships between atypical psychosis, SZ and BD were then assessed using independent GWAS data. Forty-seven patients with solid criteria of atypical psychosis and 882 normal controls (NCs) were scanned using an Affymetrics 6.0 chip. GWAS SZ data (560 SZ cases and 548 NCs) and GWAS BD (107 cases with BD type 1 and 107 NCs) were compared using gene-based analysis. The most significant SNPs were detected around the CHN2/CPVL genes (rs245914, P = 1.6 × 10(-7)) , COL21A1 gene (rs12196860, P = 2.45 × 10(-7) ), and PYGL/TRIM9 genes (rs1959536, P = 7.73 × 10(-7) ), although none of the single-nucleotide polymorphisms exhibited genome-wide significance (P = 5 × 10(-8) ). One of the highest peaks was detected on the major histocompatibility complex region, where large SZ GWASs have previously disclosed an association. The gene-based analysis suggested significant enrichment between SZ and atypical psychosis (P = 0.01), but not BD. This study provides clues about the types of patient whose diagnosis lies between SZ and BD. Studies with larger samples are required to determine the causal variant.

Emerging trends in antipsychotic and antidepressant drug development: Targeting nonmonoamine receptors and innovative mechanisms.

The domain of psychiatric drug development is currently witnessing a notable transformation, with a paramount emphasis on targeting nonmonoamine receptors and exploring inventive mechanisms of action. This paper presents an overview of the ongoing advancements in antipsychotic and antidepressant drug development. Historically, antipsychotics predominantly targeted dopamine receptors, but there is now an escalating interest in drugs that act on alternative receptors, exemplified by the TAAR1 receptor. One noteworthy candidate is Ulotaront (SEP-363856), an agent acting as a TAAR1 agonist with 5-HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side-effects. Similarly, MIN-101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)-approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor-positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK-653 (NBI-1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric modulation, respectively. This paper underscores the transformative potential of these novel drug candidates in psychiatric treatment and their ability to address cases that were previously treatment-resistant. By focusing on nonmonoamine receptors and introducing innovative mechanisms, these drugs offer a promising prospect of improved outcomes for individuals suffering from schizophrenia and MDD. Thus, sustained attention and dedication to the development of such drugs are essential to augmenting the therapeutic options available for psychiatric patients.

Current practice for clozapine-induced leukopenia in Japanese psychiatric hospitals: A nationwide survey.

Clozapine is an atypical antipsychotic used for treatment-resistant schizophrenia. In Japan, its use requires management by a blood monitoring system called the Clozaril Patient Monitoring Service (CPMS) for the early detection of serious side effects such as agranulocytosis, which is extremely rare. Monitoring services vary among the clozapine suppliers in different countries. Additionally, Japanese patients can be started on clozapine treatment exclusively through an 18-week inpatient admission at a psychiatric hospital capable of coordinating with a hematologist. One reported reason for the lack of widespread clozapine use in Japan is the difficulty in establishing collaboration with hematologists when agranulocytosis/leukopenia occurs. Hence, we conducted a nationwide web-based survey of CPMS-registered psychiatric facilities in Japan to determine the status of collaboration with hematology departments. Valid responses were received from the psychiatrists responsible for prescribing clozapine at 203 of the 547 facilities (response rate: 37.1 %). The largest number of psychiatric facilities (61 %) collaborated with hematologists at another facility with a psychiatry department, while psychiatrists in 32 % of the facilities worked with hematologists at their own facilities. Most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist. The actual workload of hematologists was limited, and the patients might experience the burden of repeated blood sampling. This study suggests that disseminating information regarding the status of collaborations with hematologists may promote the widespread use of clozapine in Japan. SHORT COMMENT FOR TWITTER: This study suggests that most patients with clozapine-induced agranulocytosis/leukopenia could be treated with clozapine discontinuation and follow-up in psychiatric inpatient units with the assistance of a hematologist.

Development and acceptability testing of a decision aid for considering whether to reduce antipsychotics in individuals with stable schizophrenia.

AIM: Continued antipsychotic treatment is the key to preventing relapse. Maintenance antipsychotic monotherapy and optimal dose use are recommended for individuals with stable schizophrenia because of their undesirable effects. Decision aids (DAs) are clinical conversation tools that facilitate shared decision-making (SDM) between patients and health-care providers. This study aimed to describe the development process and results of acceptability testing of a DA for individuals with stable schizophrenia, considering (i) whether to continue high-dose antipsychotics or reduce to the standard dose and (ii) whether to continue two antipsychotics or shift to monotherapy. METHODS: A DA was developed according to the guidelines for the appropriate use of psychotropic medications and International Patient Decision Aid Standards (IPDAS). First, a DA prototype was developed based on a previous systematic review and meta-analysis conducted for identifying the effects of continuing or reducing antipsychotic treatment. Second, mixed-method survey was performed among individuals with schizophrenia and health-care providers to modify and finalize the DA. RESULTS: The DA consisted of an explanation of schizophrenia, options to continue high-dose antipsychotics or reduce to the standard dose, options to continue two antipsychotics or shift to monotherapy, pros and cons of each option, and a value-clarification worksheet for each option. The patients (n = 20) reported acceptable language use (75%), adequate information (75%), and well-balanced presentation (79%). Health-care providers (n = 20) also provided favorable overall feedback. The final DA covered six IPDAS qualifying criteria. CONCLUSION: A DA was successfully developed for schizophrenia, considering whether to reduce antipsychotics, which can be used in the SDM process.