Impaired migration of autologous induced neural stem cells from patients with schizophrenia and implications for genetic risk for psychosis.

Stem cell technologies have presented explicit evidence of the neurodevelopmental hypothesis of schizophrenia. However, few studies investigated relevance of the schizophrenia genetic liability and the use of genetic reprogramming on pluripotent stem cells to the impaired neurodevelopment shown by stem cells. Therefore, this study sought to investigate the cellular phenotypes of induced neural stem cells (iNSCs) derived without genetic modification from patients with schizophrenia and from genetic high risk (GHR) individuals. Three patients with a diagnosis of schizophrenia, 3 GHR individuals who had two or more relatives with schizophrenia, and 3 healthy volunteers participated. iNSCs were derived using a small molecule-based lineage switch method, and their gene expression levels and migration capabilities were examined. Demographic characteristics were not different among the groups (age, χ2 = 5.637, P = .060; education, χ2 = 2.111, P = .348). All participants stayed well during the follow-up except one GHR individual who developed psychosis 1.5 years later. Migration capacity was impaired in iNSCs from patients with schizophrenia (SZ-iNSCs) compared to iNSCs from GHR individuals or controls (P < .001). iNSCs from a GHR individual who later developed schizophrenia showed migratory impairment that was similar to SZ-iNSCs. Gene expression levels of Sox2 in SZ-iNSCs were significantly lower than those in controls (P = .028). Defective migration in genetically unmodified SZ-iNSCs is the first direct demonstration of neurodevelopmental abnormalities in schizophrenia. Additionally, alterations in gene expression in SZ-iNSCs suggest mechanisms by which genetic liability leads to aberrant neurodevelopment.

A Prospective Study for Prediction of Psychotic Relapse Using the Korean Early Signs Scale in Patients With Schizophrenia.

INTRODUCTION: A psychotic relapse of schizophrenia is commonly preceded by nonpsychotic behavioral symptoms and signs, and detection of these early signs may enable prevention of relapse of schizophrenia. This study aimed to test the predictive validity of a Korean version of Early Signs Scale (K-ESS) for psychotic relapse for detecting the early signs. MATERIALS AND METHODS: In this multicenter noninterventional 52-week prospective study, outpatients diagnosed as having schizophrenia within 5 years were recruited. The K-ESS and Clinical Global Impression-Severity (CGI-S) scale were administered monthly until the end of the study or the relapse. The primary objective was to determine an optimal cutoff point of K-ESS score for prediction of psychotic relapse. The secondary objective was to assess the concurrent validity of the K-ESS using CGI-S scale. RESULTS: Among the 162 included patients, 14 (8.6%) relapsed during the 52-week study period. The optimal cutoff score of K-ESS was 15 with a sensitivity of 71.43% and a specificity of 52.70%, indicating poor predictive accuracy of K-ESS. A lower cutoff K-ESS score of 3 and a higher cutoff score of 28 were found in the subgroups with milder (CGI-S = 1-2) and severer (CGI-S = 3-4) symptom severity, respectively, with fair to good predictive accuracy. The K-ESS showed acceptable concurrent validity with CGI-S and concordance rate between self-rated and informant-rated scores. DISCUSSION: The predictive accuracy of K-ESS was limited by evaluation interval of a month. At least fortnightly follow-up would be needed for detection of early signs to prevent a psychotic relapse in schizophrenia.

Cortical Volumetric Correlates of Childhood Trauma, Anxiety, and Impulsivity in Bipolar Disorder.

OBJECTIVE: More recently, attention has turned to the linkage between childhood trauma and emotional dysregulation, but the evidence in bipolar disorder (BD) is limited. To determine neurobiological relationships between childhood trauma, current anxiety, and impulsivity, we investigated cortical volumetric correlates of these clinical factors in BD. METHODS: We studied 36 patients with DSM-5 BD and 29 healthy controls. Childhood trauma, coexisting anxiety, and impulsivity were evaluated with the Korean version-Childhood Trauma Questionnaire (CTQ), the Korean version-Beck Anxiety Inventory (BAI), and the Korean version-Barratt Impulsiveness Scale (BIS). Voxel-based morphometry (VBM) was used to assess gray matter volume (GMV) alterations on the brain magnetic resonance imaging (MRI). Partial correlation analyses were conducted to examine associations between the GMV and each scale in the BD group. RESULTS: Childhood trauma, anxiety, and impulsivity were interrelated in BD. BD patients revealed significant inverse correlations between the GMV in the right precentral gyrus and CTQ scores (r=-0.609, p<0.0003); between the GMV in the left middle frontal gyrus and BAI scores (r=-0.363, p=0.044). Moreover, patients showed similar tendency of negative correlations between the GMV in the right precentral gyrus and BIS scores; between the GMV in the left middle frontal gyrus and CTQ scores. CONCLUSION: The present study provides evidence for a neural basis between childhood trauma and affect regulations in BD. The GMV alterations in multiple frontal lobe areas may represent neurobiological markers for anticipating the course of BD.

Diagnostic value of structural and diffusion imaging measures in schizophrenia.

Objectives: Many studies have attempted to discriminate patients with schizophrenia from healthy controls by machine learning using structural or functional MRI. We included both structural and diffusion MRI (dMRI) and performed random forest (RF) and support vector machine (SVM) in this study. Methods: We evaluated the performance of classifying schizophrenia using RF method and SVM with 504 features (volume and/or fractional anisotropy and trace) from 184 brain regions. We enrolled 47 patients and 23 age- and sex-matched healthy controls and resampled our data into a balanced dataset using a Synthetic Minority Oversampling Technique method. We randomly permuted the classification of all participants as a patient or healthy control 100 times and ran the RF and SVM with leave one out cross validation for each permutation. We then compared the sensitivity and specificity of the original dataset and the permuted dataset. Results: Classification using RF with 504 features showed a significantly higher rate of performance compared to classification by chance: sensitivity (87.6% vs. 47.0%) and specificity (95.9 vs. 48.4%) performed by RF, sensitivity (89.5% vs. 48.0%) and specificity (94.5% vs. 47.1%) performed by SVM. Conclusions: Machine learning using RF and SVM with both volume and diffusion measures can discriminate patients with schizophrenia with a high degree of performance. Further replications are required.

Abnormal asymmetry of white matter tracts between ventral posterior cingulate cortex and middle temporal gyrus in recent-onset schizophrenia.

INTRODUCTION: Previous studies have reported abnormalities in the ventral posterior cingulate cortex (vPCC) and middle temporal gyrus (MTG) in schizophrenia patients. However, it remains unclear whether the white matter tracts connecting these structures are impaired in schizophrenia. Our study investigated the integrity of these white matter tracts (vPCC-MTG tract) and their asymmetry (left versus right side) in patients with recent onset schizophrenia. METHOD: Forty-seven patients and 24 age-and sex-matched healthy controls were enrolled in this study. We extracted left and right vPCC-MTG tract on each side from T1W and diffusion MRI (dMRI) at 3T. We then calculated the asymmetry index of diffusion measures of vPCC-MTG tracts as well as volume and thickness of vPCC and MTG using the formula: 2×(right-left)/(right+left). We compared asymmetry indices between patients and controls and evaluated their correlations with the severity of psychiatric symptoms and cognition in patients using the Positive and Negative Syndrome Scale (PANSS), video-based social cognition scale (VISC) and the Wechsler Adult Intelligence Scale (WAIS-III). RESULTS: Asymmetry of fractional anisotropy (FA) and radial diffusivity (RD) in the vPCC-MTG tract, while present in healthy controls, was not evident in schizophrenia patients. Also, we observed that patients, not healthy controls, had a significant FA decrease and RD increase in the left vPCC-MTG tract. There was no significant association between the asymmetry indices of dMRI measures and IQ, VISC, or PANSS scores in schizophrenia. CONCLUSION: Disruption of asymmetry of the vPCC-MTG tract in schizophrenia may contribute to the pathophysiology of schizophrenia.

Early referral and comorbidity as possible causes of the declining transition rate in subjects at clinical high risk for psychosis.

AIM: A clinical high risk (CHR) for psychosis is regarded as the state of being at risk of developing psychosis. However, the rate of transition to psychosis among CHR subjects has been declining over time. We aimed to investigate the effects of the possible causes of the declining transition rate. METHODS: A total of 129 CHR subjects were divided into two groups according to the date of enrollment: the 2005-2009 group and the 2009-2013 group. Baseline demographic and clinical characteristics, including medication prescription, were compared. The duration of untreated prodromal positive symptoms (DUPP) was used to account for early referral. RESULTS: The transition rate to psychosis in the 2009-2013 group was significantly lower than that in the 2005-2009 group (χ2 = 4.664, P = 0.031), although the risk factors of transition, intelligence quotient and prodromal positive symptoms did not differ between the two groups. When the DUPP was added to the follow-up duration, the between-group difference in the transition rates was no longer significant; however, the P-value was low (χ2 = 2.761, P = 0.097). After adjusting for axis II comorbidities other than schizotypal personality disorder, the effect of group division on the transition rate disappeared; however, the P-value was also low (P = 0.072). The mean olanzapine equivalent dose and the proportion of subjects prescribed with antidepressant or anxiolytic did not differ between the two groups. CONCLUSIONS: Early referral and axis II comorbidities other than schizotypal personality disorder were associated with the declining transition rate.

Small molecule-based lineage switch of human adipose-derived stem cells into neural stem cells and functional GABAergic neurons.

Cellular reprogramming using small molecules (SMs) without genetic modification provides a promising strategy for generating target cells for cell-based therapy. Human adipose-derived stem cells (hADSCs) are a desirable cell source for clinical application due to their self-renewal capacity, easy obtainability and the lack of safety concerns, such as tumor formation. However, methods to convert hADSCs into neural cells, such as neural stem cells (NSCs), are inefficient, and few if any studies have achieved efficient reprogramming of hADSCs into functional neurons. Here, we developed highly efficient induction protocols to generate NSC-like cells (iNSCs), neuron-like cells (iNs) and GABAergic neuron-like cells (iGNs) from hADSCs via SM-mediated inhibition of SMAD signaling without genetic manipulation. All induced cells adopted morphological, molecular and functional features of their bona fide counterparts. Electrophysiological data demonstrated that iNs and iGNs exhibited electrophysiological properties of neurons and formed neural networks in vitro. Microarray analysis further confirmed that iNSCs and iGNs underwent lineage switch toward a neural fate. Together, these studies provide rapid, reproducible and robust protocols for efficient generation of functional iNSCs, iNs and iGNs from hADSCs, which have utility for modeling disease pathophysiology and providing cell-therapy sources of neurological disorders.

Prescription Pattern of Antidepressants for Children and Adolescents in Korea Based on Nationwide Data.

Antidepressant prescription for youths has recently been on the increase. There is a growing concern over the increasing off-label usage of antidepressants. Current data on off-label antidepressant usage vary across countries and healthcare systems. Therefore, we examined the extent and pattern of antidepressant prescription for Korean children and adolescents using population-based data. Our data was retrieved from the Korean National Health Insurance Service National Sample Cohort of the year 2013. Among 0.2 million children and adolescents aged 6-18 years from the cohort, subjects who had received any antidepressant medication in the year 2013 were investigated for the prescribed medication, concomitant psychotropic medication, and the associated diagnosis. A total of 2,190 children and adolescents (boys, 55.4%) received antidepressant medication. The most common diagnosis was depressive disorders (n = 469, 21.4%), followed by attention-deficit/hyperactivity disorder (n = 442, 20.2%). Among the prescriptions (n = 3,370), escitalopram (n = 650, 24.1%) and fluoxetine (n = 553, 20.5%) were the two most frequently prescribed drugs. A majority of prescriptions (n = 2,039, 60.5%) included concomitant psychotropic agents, consisting of antipsychotics (n = 901, 26.7%), sedatives (n = 263, 26.3%), medication for attention-deficit/hyperactivity disorder (n = 822, 24.4%), and some others. Our study shows the prescription pattern of antidepressants for children and adolescents in Korea, of which a large proportion is off-label. The results call for close monitoring by clinicians treating this population.

Regional Differences in Serotonin Transporter Occupancy by Escitalopram: An [11C]DASB PK-PD Study.

BACKGROUND AND OBJECTIVE: Escitalopram is one of the most commonly prescribed selective serotonin reuptake inhibitors (SSRIs). It is thought to act by blocking the serotonin transporter (SERT). However, its dose-SERT occupancy relationship is not well known, so it is not clear what level of SERT blockade is achieved by currently approved doses. METHODS: To determine the dose-occupancy relationship, we measured serial SERT occupancy using [11C]DASB [3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] positron emission tomography (PET) and plasma drug concentrations after the administration of escitalopram in 12 healthy volunteers. We then built a pharmacokinetic-pharmacodynamic model to characterize the dose-occupancy relationship in the putamen and the dorsal raphe nucleus. RESULTS: Escitalopram at approved doses occupied less SERT than expected and the SERT occupancy showed regional effects [occupancy was higher in the dorsal raphe nucleus than in the putamen (p < 0.001)]. The drug concentration when 50 % of receptors are occupied (EC50) value and Hill coefficient were significantly different between the putamen (EC50 4.30, Hill coefficient 0.459) and the dorsal raphe nucleus (EC50 2.89, Hill coefficient 0.817). CONCLUSIONS: Higher doses of escitalopram than 20 mg are needed to achieve 80 % or greater SERT occupancy. Higher occupancy by escitalopram in the dorsal raphe nucleus relative to the striatum may explain the delayed onset of action of SSRIs by modulating autoreceptor function. The prevention of the 5-HT1A autoreceptor-mediated negative feedback could be a strategy for accelerating the clinical antidepressant effects.

Individualized covariance profile of cortical morphology for auditory hallucinations in first-episode psychosis.

Neocortical phenotype of cortical surface area (CSA) and thickness (CT) are influenced by distinctive genetic factors and undergo differential developmental trajectories, which could be captured using the individualized cortical structural covariance (ISC). Disturbed patterns of neocortical development and maturation underlie the perceptual disturbance of psychosis including auditory hallucination (AH). To demonstrate the utility of selected ISC features as primal biomarker of AH in first-episode psychosis (FEP) subjects experiencing AH (FEP-AH), we employed herein a support vector machine (SVM). A total of 147 subjects (FEP-AH, n = 27; FEP-NAH, n = 24; HC, n = 96) underwent T1 -weighted magnetic resonance imaging at 3T. The FreeSurfer software suite was used for cortical parcellation, with the CSA-ISC and CT-ISC then calculated. The most informative ISCs showing statistical significance (P < 0.001) across every run of leave-one-out group-comparison were aligned according to the absolute value of averaged t-statistics and were packaged into candidate feature sets for classification analysis using the SVM. An optimal feature set comprising three CSA-ISCs, including the intraparietal sulcus, Broca's complex, and the anterior insula, distinguished FEP-AH from FEP-NAH subjects with 83.6% accuracy (sensitivity = 82.8%; specificity = 85.7%). Furthermore, six CT-ISCs encompassing the executive control network and Wernicke's module classified FEP-AH from FEP-NAH subjects with 82.3% accuracy (sensitivity = 79.5%; specificity = 88.6%). Finally, extended sets of ISCs related to the default-mode network distinguished FEP-AH or FEP-NAH from HC subjects with 89.0-93.0% accuracy (sensitivity = 88.4-93.4%; specificity = 89.0-94.1%). This study established a distinctive intermediate phenotype of biological proneness for AH in FEP using CSA-ISCs as well as a state marker of disease progression using CT-ISCs.

Parental socioeconomic status and prognosis in individuals with ultra-high risk for psychosis: A 2-year follow-up study.

A possible relationship between socioeconomic status (SES) and the development of mental illness has been continuously suggested. Still, less clear is whether the SES has a direct effect on the development of schizophrenia. In this longitudinal study, we test the hypothesis that parental SES is associated with the prognosis of individuals at ultra-high risk (UHR) for psychosis. One hundred and sixteen individuals who were determined as UHR using a Comprehensive Assessment of At-Risk Mental States (CAARMS) were classified into three groups based on the parental SES levels assessed by the Hollingshead-Redlich scale. There were no differences in the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS) at baseline. However, at the 1-year follow-up, the higher versus lower SES group showed significant differences in clinical measures including SAPS, SANS, PANSS positive and negative scales as well as BPRS scores. Most of these clinical differences were attenuated by the second year of follow-up with no sign of an increased rate of conversion to psychosis derived from a socioeconomically disadvantaged status. However, SAPS and PANSS positive scale still revealed sub-threshold positive symptoms within the low SES group at the 2-year follow-up. Moreover, especially for the subjects who continued the follow-ups for 1year and/or 2years, the changes of clinical symptoms between the baseline and follow-ups showed that there were significant symptom changes in higher and middle SES groups within the 1-year period already, but the lower SES group showed significant recovery at the second year. Our findings suggest that low parental SES can be detrimental to the prognosis phase of individuals at UHR. Limited supportive socioeconomic resources may slow the rate of symptom recovery in UHR subjects.

Factors contributing to the duration of untreated prodromal positive symptoms in individuals at ultra-high risk for psychosis.

Individuals at ultra-high risk (UHR) for psychosis experience a considerable delay before appropriate clinical attention is provided. Therefore, we investigated the correlates of this delay by examining clinical, socio-demographic and neuropsychological contributors to the duration of untreated prodromal positive symptoms (DUPP) in them (n=73). The slowly progressive mode of functional decline, defined as a small percentage drop in the Global Assessment of Functioning (GAF) score within the past year, and male gender, explained a considerable portion of the DUPP in the multivariate regression model (F=9.269, p<0.001). Slower functional decline may be correlated with delayed care during the UHR period.

MRI study of the cavum septum pellucidum in obsessive-compulsive disorder.

The cavum septum pellucidum (CSP), a putative marker of neurodevelopmental anomaly, has been associated with an increased risk of several psychiatric disorders. The purpose of this study was to evaluate the CSP in patients with obsessive-compulsive disorder (OCD) compared with healthy control subjects. Seventy-one patients with OCD and 71 healthy volunteers matched for age and sex were evaluated with magnetic resonance imaging. We evaluated the CSP using criteria employed in previous studies: presence of the CSP, length of the CSP, and overall size of the CSP, measured in five grades, ranging from grades 0 (no CSP) to 4 (severe CSP). We evaluated OCD symptom severity using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The CSP presence was significantly greater in the OCD group (60.6%) than in control subjects (29.6%), and CSP size grade was significantly larger in the OCD group (chi(2) = 15.609, P = 0.004). CSP length showed no significant group difference. Among patients with OCD, those with a CSP had higher scores on the obsession subscale of the Y-BOCS than those without a CSP (Z = -2.358, P = 0.018), while they did not show significant difference from those without a CSP in the compulsion subscale of the Y-BOCS, age, duration of illness, or age at onset. These results indicate that neurodevelopmental alterations in midline structures might contribute to the pathogenesis of OCD.

Gender difference in the prodromal symptoms of first-episode schizophrenia.

To investigate the gender difference of early symptoms appearing before the onset of the psychotic symptoms in patients with first-episode schizophrenia, we reviewed the medical records of 63 patients (38 males, 25 females), who were hospitalized for first-episode schizophrenia. The frequency and duration of prodromal and psychotic symptoms, Clinical Global Impression scale scores, Global Assessment of Functioning (GAF) scale scores at admission, and other clinical characteristics were recorded for all patients. Overall, the most common prodromal symptoms were attenuated positive symptoms (89%), followed by mood symptoms (86%). Negative symptoms were the most common in male patients (97.4%), whereas attenuated positive symptoms were the most common in female patients (84%). Male patients demonstrated more frequent negative, cognitive, and obsessive-compulsive symptoms than female patients did and also showed a tendency of having negative symptoms for the longer period. Correlational analysis showed a significant negative correlation between the duration of negative symptoms and GAF scores at admission in male patients. Our findings suggest that different patterns of prodromal symptoms between male and female begin before the onset of the psychosis. Further prospective studies should be needed.

Cavum septum pellucidum in subjects at ultra-high risk for psychosis: compared with first-degree relatives of patients with schizophrenia and healthy volunteers.

OBJECTIVE: The cavum septum pellucidum (CSP) is a space between the two leaflets of the septum pellucidum, and is a putative marker of disturbance in early brain development. We examined whether CSP was present more frequently in subjects at ultra-high risk (UHR) for psychosis compared to first-degree relatives of patients with schizophrenia (genetic high risk, GHR) and healthy controls (HC). METHODS: We evaluated CSP in 87 subjects (30 UHR, 23 GHR, and 34 HC) according to a published grading system using high-resolution magnetic resonance imaging (MRI) with 0.45-mm slice thickness. We also assessed two other criteria: presence of CSP on at least one MRI slice, and abnormally large CSP (i.e., > or =6 mm in length). Correlational analysis between CSP measures and clinical symptoms was also examined. RESULTS: Based on the grading scale, the UHR group exhibited a significantly higher incidence of abnormal CSP (grades 2, 3, and 4) compared to the HC group, but there were no significant differences in the incidence of abnormal CSP between the UHR and GHR or the GHR and HC groups. There were no significant differences among the groups in the presence of CSP on at least one MRI slice or abnormally large CSP based on the length of CSP. In addition, no significant correlations between CSP measures and clinical symptoms were found. CONCLUSION: These findings suggest that abnormal CSP might be associated with susceptibility to psychosis, although the CSP itself might be a normal anatomical variant. Further studies using a larger sample are needed to clarify issues on neurodevelopmental perspective in subjects at high risk for psychosis.