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Aim: Subjective quality of life is a clinically relevant outcome that is strongly associated with the severity of clinical symptoms in individuals with ultra‐high risk for psychosis and patients with recent‐onset psychotic disorder. Our objective was to examine whether longitudinal changes in clinical symptoms are associated with quality of life in ultra‐high risk individuals and patients with recent‐onset psychotic disorder. Methods: Individuals with ultra‐high risk and patients with recent‐onset psychosis disorder were recruited in the same clinical settings at baseline and were followed up with more than 6 months and less than 5 years later. We assessed five factors of clinical symptoms using the positive and negative syndrome scale, and quality of life using the World Health Organization quality of life questionnaire‐short form. We used multiple regression to examine the relationships between clinical symptoms and quality of life while controlling for diagnosis, follow‐up period, age, and sex. Results: Data were collected from 22 individuals with ultra‐high risk and 27 patients with recent‐onset psychosis disorder. The multiple regression analysis results indicated that the more severe anxiety/depression was at baseline, the poorer the quality of life at follow‐up. Further, improvement of anxiety/depression and disorganized thoughts were associated with improvement in quality of life. The difference in diagnosis did not affect the association between clinical symptoms and quality of life. Conclusion: These findings suggest that the improvement of anxiety/depression and disorganized thoughts is important in the early stages of psychosis before it becomes severe, affecting the quality of life. [ABSTRACT FROM AUTHOR]

Aim: Information processing is supported by the cortico‐cortical transmission of neural oscillations across brain regions. Recent studies have demonstrated that the rhythmic firing of neural populations is not random but is governed by interactions with other frequency bands. Specifically, the amplitude of gamma‐band oscillations is associated with the phase of lower frequency oscillations in support of short and long‐range communications among networks. This cross‐frequency relation is thought to reflect the temporal coordination of neural communication. While schizophrenia patients show abnormal oscillatory responses across multiple frequencies at rest, it is unclear whether the functional relationships among frequency bands are intact. This study aimed to characterize the lower frequency (delta/theta, 1–8 Hz) phase and the amplitude of gamma oscillations in healthy subjects and schizophrenia patients at rest. Methods: Low frequency‐phase (delta‐ and theta‐ band) angles and gamma‐band amplitude relationships were assessed in 142 schizophrenia patients and 128 healthy subjects. Results: Significant low‐frequency phase alteration related to high‐power gamma was detected across broadly distributed scalp regions in both healthy subjects and patients. In patients, delta phase synchronization related to high‐power gamma was significantly decreased at the frontocentral, right middle temporal, and left temporoparietal electrodes but significantly increased at the left parietal electrode. Conclusions: High‐power gamma‐related delta phase alteration may reflect a core pathophysiologic abnormality in schizophrenia. Data‐driven measures of functional relationships among frequency bands may prove useful in the development of novel therapeutics. Future studies are needed to determine whether these alterations are specific to schizophrenia or appear in other neuropsychiatric patient populations. [ABSTRACT FROM AUTHOR]

Reproducibility is one of the most important issues for generalizing the results of clinical research; however, low reproducibility in neuroimaging studies is well known. To overcome this problem, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium, an international neuroimaging consortium, established standard protocols for imaging analysis and employs either meta‐ and mega‐analyses of psychiatric disorders with large sample sizes. The Cognitive Genetics Collaborative Research Organization (COCORO) in Japan promotes neurobiological studies in psychiatry and has successfully replicated and extended works of ENIGMA especially for neuroimaging studies. For example, (a) the ENIGMA consortium showed subcortical regional volume alterations in patients with schizophrenia (n = 2,028) compared to controls (n = 2,540) across 15 cohorts using meta‐analysis. COCORO replicated the volumetric changes in patients with schizophrenia (n = 884) compared to controls (n = 1,680) using the ENIGMA imaging analysis protocol and mega‐analysis. Furthermore, a schizophrenia‐specific leftward asymmetry for the pallidum volume was demonstrated; and (b) the ENIGMA consortium identified white matter microstructural alterations in patients with schizophrenia (n = 1,963) compared to controls (n = 2,359) across 29 cohorts. Using the ENIGMA protocol, a study from COCORO showed similar results in patients with schizophrenia (n = 696) compared to controls (n = 1,506) from 12 sites using mega‐analysis. Moreover, the COCORO study found that schizophrenia, bipolar disorder (n = 211) and autism spectrum disorder (n = 126), but not major depressive disorder (n = 398), share similar white matter microstructural alterations, compared to controls. Further replication and harmonization of the ENIGMA consortium and COCORO will contribute to the generalization of their research findings. [ABSTRACT FROM AUTHOR]

The underlying pathologies of psychiatric disorders, which cause substantial personal and social losses, remain unknown, and their elucidation is an urgent issue. To clarify the core pathological mechanisms underlying psychiatric disorders, in addition to laboratory‐based research that incorporates the latest findings, it is necessary to conduct large‐sample‐size research and verify reproducibility. For this purpose, it is critical to conduct multicenter collaborative research across various fields, such as psychiatry, neuroscience, molecular biology, genomics, neuroimaging, cognitive science, neurophysiology, psychology, and pharmacology. Moreover, collaborative research plays an important role in the development of young researchers. In this respect, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium and Cognitive Genetics Collaborative Research Organization (COCORO) have played important roles. In this review, we first overview the importance of multicenter collaborative research and our target psychiatric disorders. Then, we introduce research findings on the pathophysiology of psychiatric disorders from neurocognitive, neurophysiological, neuroimaging, genetic, and basic neuroscience perspectives, focusing mainly on the findings obtained by COCORO. It is our hope that multicenter collaborative research will contribute to the elucidation of the pathological basis of psychiatric disorders. [ABSTRACT FROM AUTHOR]

Aim: Gamma‐band auditory steady‐state response (ASSR) is a neurophysiologic index that is increasingly used as a translational biomarker in the development of treatments of neuropsychiatric disorders. While gamma‐band ASSR is generated by distributed networks of highly interactive temporal and frontal cortical sources, the majority of human gamma‐band ASSR studies using electroencephalography (EEG) highlight activity from only a single frontocentral scalp site, Fz, where responses tend to be largest and reductions in schizophrenia patients are most evident. However, no previous study has characterized the relative source contributions to Fz, which is a necessary step to improve the concordance of preclinical and clinical EEG studies. Methods: A novel method to back‐project the contributions of independent cortical source components was applied to assess the independent sources and their proportional contributions to Fz as well as source‐resolved responses in 432 schizophrenia patients and 294 healthy subjects. Results: Independent contributions of gamma‐band ASSR to Fz were detected from orbitofrontal, bilateral superior/middle/inferior temporal, bilateral middle frontal, and posterior cingulate gyri in both groups. In contrast to expectations, the groups showed comparable source contribution weight to gamma‐band ASSR at Fz. While gamma‐band ASSR reductions at Fz were present in schizophrenia patients consistent with previous studies, no group differences in individual source‐level responses to Fz were detected. Conclusion: Small differences in multiple independent sources summate to produce scalp‐level differences at Fz. The identification of independent source contributions to a single scalp sensor represents a promising methodology for measuring dissociable and homologous biomarker targets in future translational studies. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, "bottom-up" effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Clozapine-induced pemphigus successfully treated with methylprednisolone pulse without discontinuation of clozapine: a case report The medication was tapered, and clozapine was begun on day X; on day X + 7, stomatitis appeared; on day X + 21, clozapine was increased to 200 mg. Auditory hallucination was significantly improved by clozapine, and oral mucosal legions had stayed remitted without the discontinuation of clozapine. [Extracted from the article]

Background: Patients with schizophrenia show abnormal spontaneous oscillatory activity in scalp-level electroencephalographic (EEG) responses across multiple frequency bands. While oscillations play an essential role in the transmission of information across neural networks, few studies have assessed the frequency-specific dynamics across cortical source networks at rest. Identification of the neural sources and their dynamic interactions may improve our understanding of core pathophysiologic abnormalities associated with the neuropsychiatric disorders. Methods: A novel multivector autoregressive modeling approach for assessing effective connectivity among cortical sources was developed and applied to resting-state EEG recordings obtained from n = 139 schizophrenia patients and n = 126 healthy comparison subjects. Results: Two primary abnormalities in resting-state networks were detected in schizophrenia patients. The first network involved the middle frontal and fusiform gyri and a region near the calcarine sulcus. The second network involved the cingulate gyrus and the Rolandic operculum (a region that includes the auditory cortex). Conclusions: Schizophrenia patients show widespread patterns of hyper-connectivity across a distributed network of the frontal, temporal, and occipital brain regions. Results highlight a novel approach for characterizing alterations in connectivity in the neuropsychiatric patient populations. Further mechanistic characterization of network functioning is needed to clarify the pathophysiology of neuropsychiatric and neurological diseases. [ABSTRACT FROM AUTHOR]

Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4 , whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles. [ABSTRACT FROM AUTHOR]

Objective Disruptions in the dopamine system have been observed in psychiatric disorders. Since dopamine is mainly produced in the ventral tegmental area (VTA), elucidating the differences in the VTA neural network across psychiatric disorders would facilitate a greater understanding of the pathophysiological mechanisms underlying these disorders. However, no study has compared VTA-seed-based functional connectivity across psychiatric disorders. Therefore, we conducted a resting-state functional magnetic resonance imaging (rs-fMRI) study to perform a seed-based fMRI analysis, using the VTA as a seed. Methods We included participants with major depressive disorder (MDD; n = 45), schizophrenia (n = 32), and bipolar disorder (BPD; n = 30), along with healthy control participants (n = 46) who were matched for age, gender, and handedness. Results The results showed that patients with MDD and BPD had altered VTA-related connectivity in the superior frontal gyrus, frontal pole regions, hippocampus, cerebellum, and posterior cingulate cortex. Some of these differences in connectivity were also found between affective disorders and schizophrenia; however, there were no differences between the schizophrenia and control groups. Connectivity between the VTA and the hippocampus was correlated with positive symptoms in the schizophrenia group. The connectivity was not associated with medication dose, and the results remained significant after controlling for dose. Conclusions The results suggest that altered brain functional connectivity related to VTA networks could be associated with the distinctive pathophysiologies of psychiatric disorders, especially affective disorders. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia patients exhibit cognitive deficits across multiple domains, including verbal memory, working memory, and executive function, which substantially contribute to psychosocial disability. Gamma oscillations are associated with a wide range of cognitive operations, and are important for cortico-cortical transmission and the integration of information across neural networks. While previous reports have shown that schizophrenia patients have selective impairments in the ability to support gamma oscillations in response to 40-Hz auditory stimulation, it is unclear if patients show abnormalities in gamma power at rest, or whether resting-state activity in other frequency bands is associated with cognitive functioning in schizophrenia patients. Methods: Resting-state electroencephalogram (EEG) was assessed over 3 min in 145 healthy comparison subjects and 157 schizophrenia patients. Single-word reading ability was measured via the reading subtest of the Wide Range Achievement Test-3 (WRAT). Auditory attention and working memory were evaluated using Letter-Number Span and Letter-Number Sequencing. Executive function was assessed via perseverative responses on the Wisconsin Card Sorting Test (WCST). Verbal learning performance was measured using the California Verbal Learning Test second edition (CVLT-II). Results: Schizophrenia patients showed normal levels of delta-band power but abnormally elevated EEG power in theta, alpha, beta, and gamma bands. An exploratory correlation analysis showed a significant negative correlation of gamma-band power and verbal learning performance in schizophrenia patients. Conclusions: Patients with schizophrenia have abnormal resting-state EEG power across multiple frequency bands; gamma-band abnormalities were selectively and negatively associated with impairments in verbal learning. Resting-state gamma-band EEG power may be useful for understanding the pathophysiology of cognitive dysfunction and developing novel therapeutics in schizophrenia patients. [ABSTRACT FROM AUTHOR]

Mismatch negativity (MMN) is a negative deflection of the auditory event-related potential (ERP) elicited by an abrupt change in a sound presented repeatedly. In patients with schizophrenia, MMN is consistently reduced, which makes it a promising biomarker. A non-human primate (NHP) model of MMN based on scalp electroencephalogram (EEG) recordings can provide a useful translational tool, given the high structural homology of the prefrontal and auditory cortices between NHPs, such as macaques, and humans. However, in previous MMN studies, the NHP models used did not allow for comparison with humans because of differences in task settings. Moreover, duration-deviant MMN (dMMN), whose reduction is larger than that in the frequency-deviant MMN (fMMN) in patients with schizophrenia, has never been demonstrated in NHP models. In this study, we determined whether dMMN can be observed in macaque scalp EEG recordings. EEGs were recorded from frontal electrodes (Fz) in two Japanese macaques. Consistent with clinical settings, auditory stimuli consisted of two pure tones, a standard and a deviant tone, in an oddball paradigm. The deviant and standard tones differed in duration (50 and 100 ms for the standard and deviant tones, respectively). A robust dMMN with a latency of around 200 ms, comparable to that in humans, was observed in both monkeys. A comparison with fMMN showed that the dMMN latency was the longer of the two. By bridging the gap between basic and clinical research, our results will contribute to the development of innovative therapeutic strategies for schizophrenia. [ABSTRACT FROM AUTHOR]

Background: In the early intervention in psychosis, ultra-high risk (UHR) criteria have been used to identify individuals who are prone to develop psychosis. Although the transition rate to psychosis in individuals at UHR is 10% to 30% within several years, some individuals at UHR present with poor prognoses even without transition occurring. Therefore, it is important to identify biomarkers for predicting the prognosis of individuals at UHR, regardless of transition. We investigated whether mismatch negativity (MMN) in response to both duration deviant stimuli (dMMN) and frequency deviant stimuli (fMMN) could predict prognosis, including remission and neurocognitive function in individuals at UHR. Materials and Methods: Individuals at UHR (n = 24) and healthy controls (HC; n = 18) participated in this study. In an auditory oddball paradigm, both dMMN and fMMN were measured at baseline. Remission and neurocognitive function after > 180 days were examined in the UHR group. Remission from UHR was defined as functional and symptomatic improvement using the Global Assessment of Functioning (GAF) score and Scale of Prodromal Symptoms (SOPS) positive subscales. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia (BACS). We examined differences in MMN amplitude at baseline between those who achieved remission (remitters) and those who did not (non-remitters). Multiple regression analyses were performed to identify predictors for functioning, positive symptoms, and neurocognitive function. Results: Compared with the HC group, the UHR group had a significantly attenuated dMMN amplitude (p = 0.003). In the UHR group, GAF scores significantly improved during the follow-up period (mean value 47.1 to 55.5, p = 0.004). The dMMN amplitude at baseline was significantly larger in the remitter (n = 6) than in the non-remitter group (n = 18) (p = 0.039). The total SOPS positive subscale scores and fMMN amplitude at baseline could predict BACS attention subscore at the follow-up point (SOPS positive subscales, p = 0.030; fMMN, p = 0.041). Conclusion: Our findings indicate that dMMN and fMMN predicted remission and neurocognitive function, respectively, in individuals at UHR, which suggests that there are both promising biomarker candidates for predicting prognosis in individuals at UHR. [ABSTRACT FROM AUTHOR]