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Objectives: Childhood trauma (ChT) is a risk factor for psychosis. Negative lifestyle factors such as rumination, negative schemas, and poor diet and exercise are common in psychosis. The present study aimed to perform a network analysis of interactions between ChT and negative lifestyle in patients and controls.Methods: We used data of patients with early-stage psychosis (n = 500) and healthy controls (n = 202). Networks were constructed using 12 nodes from five scales: the Brief Core Schema Scale (BCSS), Brooding Scale (BS), Dietary Habits Questionnaire, Physical Activity Rating, and Early Trauma Inventory Self Report-Short Form (ETI). Graph metrics were calculated.Results: The nodes with the highest predictability and expected influence in both patients and controls were cognitive (Co) and emotional domains (Em) of the BS and emotional abuse (EMO) of the ETI. The EMO was a mediator in the shortest pathway connecting the ETI and negative lifestyle for both groups. The negative other (NO) and negative self (NS) of the BCSS mediated EMO to other BCSS or BS for patients and controls, respectively.Conclusion: Our findings suggest that rumination and EMO were central symptoms in both groups and that NO and NS played important mediating roles for patients and controls, respectively.Trial Registration: ClinicalTrials.gov identifier: CUH201411002

Objective More attempts have been made recently to improve psychosocial functioning and quality of life in patients with schizophrenia, due to their crucial role in long-term outcomes. Previous studies on the effects of clozapine on psychosocial functioning have been limited in terms of generalizability and application to clinical practice. This study examined the relationship of clozapine use with psychosocial functioning and quality of life in patients with schizophrenia in a real-world setting.Methods Data were obtained from a survey targeting community-dwelling patients with schizophrenia. The Behavior and Symptom Identification Scale (BASIS) and Satisfaction with Life Scale (SWLS) were administered to evaluate psychosocial functioning and quality of life, and patients were classified into Clozapine and Non-clozapine groups. Group differences were assessed using ANCOVA, with additional sensitivity analyses for participants on atypical antipsychotic medications only.Results Of 292 patients, the Clozapine group (n=34) had significantly better psychosocial functioning and quality of life than the Nonclozapine group (n=258), as demonstrated by their low BASIS score (F=4.651, df=1, 290, p=0.032) and high SWLS score (F=14.637, df=1, 290, p

In the present study, various outcomes over 3-year period in patients with early stage psychosis including remission, recovery, relapse and medication adherence were investigated. Predictor for full recovery at year 3 was also examined. Three-year follow-up data in 534 patients with schizophrenia spectrum disorders (SSD) and psychotic disorder not otherwise specified (PNOS) were examined for overall outcome trajectories. The data of completers at year 3 (n = 157) were used to identify predictors for recovery using logistic regression. The rates of symptomatic remission and full recovery at 6-, 12-, 24-, and 36-month follow-up were 76.10, 69.20, 79.50, and 79.10%, and 22.80, 26.40, 28.60, and 39.60%, respectively. The rates of drop-out and relapse at 6-, 12-, 24-, and 36-month follow-up were 25.4, 29.5, 38.6, and 51.1%, and 3.7, 8.9, 19.0, and 38.9%, respectively. The rates of good adherence and prescription of Long-Acting Injectable Antipsychotics (LAIA) at 6-, 12-, 24- and 36-month follow-up were 87.8, 88.0, 91.9, and 93.9%, and 18.3, 21.7, 22.0, and 25.5%, respectively. Significant predictors for full recovery were duration of untreated psychosis (DUP), family intimacy and physical activity. We observed similar or better results on remission, recovery, and relapse rates compared to other previous studies. Effective psychosocial intervention should be provided to shorten the gap between remission and recovery rates and to address DUP, family issues, and exercise to enhance recovery.

Aim In the present study, the prevalence and predictors of symptomatic and full remission were investigated in patients with first-episode psychosis (FEP) at the 12-month follow-up. Methods A total of 308 participants aged 18-45 years fulfilled the study inclusion criteria and 214 completed the 12-month follow-up. Results At the 12-month follow-up, 67.3% (142) and 25.9% (55) of the FEP patients met the criteria for symptomatic and full remission, respectively. Stepwise logistic regression analysis showed a shorter duration of untreated psychosis (DUP), no family history, lower Positive and Negative Syndrome Scale (PANSS) negative symptom scores at baseline and higher familial support predicted symptomatic remission at the 12-month follow-up. A higher educational level, shorter DUP, lower PANSS general symptoms scores at baseline and higher subjective well-being under neuroleptics emotional regulation scores predicted full remission. Conclusions Our findings regarding the rates of symptomatic and full remission are consistent with previous studies. The results indicate a large discrepancy between symptomatic versus full remission rates at a 12-month follow-up in patients with FEP. Effective psychosocial interventions are necessary to improve the outcomes of FEP patients.

Purpose: Elective interval appendectomy (IA) after percutaneous catheter drainage (PCD) is traditionally advocated for perforated appendicitis with an abscess. However, this is not the only way to manage these patients when we consider the cost-effectiveness of treatment. This study compared the outcomes and cost-effectiveness of patients who underwent IA and those who underwent direct surgery. Materials and Methods: A retrospective analysis of 79 patients who were diagnosed with perforated appendicitis with abscess was conducted. We compared the hospital course, outcomes, and total medical costs between the 2 groups. Results: Forty-three patients underwent PCD insertion for the management of appendiceal abscess (IA group), and 36 underwent appendectomy (DS group). There was no significant difference in abscess size (5.67 vs. 5.35 cm, P=0.15), appendectomy method (laparoscopic/open 39/4 vs. 37/5, P=0.523), or complications (7 vs. 6 cases, P=0.963) between the 2 groups. The operation time was longer in the DS group (83.8 vs. 112.7 min, P

The Positive and Negative Syndrome Scale (PANSS) is commonly used to assess the severity of the clinical symptoms of schizophrenia (SCZ). This study aimed to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model based on therapeutic drug monitoring (TDM) data to characterize the relationship between clozapine exposure and the PANSS scores in patients with SCZ.TDM data for clozapine and PANSS scores from 45 patients with SCZ were included in this modeling analysis using NONMEM®. Based on published data, intensive PK sampling data collected up to 12 h post-dose from 23 patients was incorporated into the PK dataset to improve the fitting of absorption and disposition. For PD model development, the PANSS score was assessed at baseline, followed by 8 and 18 weeks after the initiation of clozapine dosing. Visual predictive check plots, the precision of parameter estimates, and decreases in the minimum objective function values were used for the model evaluation.A two-compartment model with an absorption lag and combined error model adequately described the PK of clozapine. The implementation of disease progression with placebo and drug effects improved the model's ability to describe the time course of the PANSS scores. In the final PK/PD model, Weibull and maximum effect (Emax) models were selected as disease progression models for the placebo and drug effect models, respectively. The model evaluation results supported the adequacy of the final model.A clozapine PK/PD model based on clinical settings adequately described the PANSS time-course in patients with SCZ. These findings may aid the development of treatment strategies for patients with SCZ.

A 61-year-old man presented with abdominal distension without any symptoms. On colonoscopy and computed tomography findings, it was clinically diagnosed as peritoneal metastasis of sigmoid colon cancer, and diagnostic laparoscopy was performed. Only the peritoneum was partially resected, and the pathology was signet ring cell carcinoma with predominantly local mucinous carcinoma component. However, the patient complained of persistent symptoms and, despite the progress of chemotherapy, the peritoneal dissemination worsened, and additional cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) was performed. Mixed adenoneuroendocrine carcinomas (MANECs) were reported in the appendix with perforated visceral peritoneum. After additional chemotherapy, the patient was discharged. Patients with advanced MANEC with peritoneal spreading may benefit from aggressive treatment by cytoreduction surgery with HIPEC, followed by intravenous chemotherapy.

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as Kicer value using [18F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BPND using [11C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in Kicer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal Kicer values and time to relapse after antipsychotic discontinuation (R2 = 0.518, p = 0.018). BPND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation.

Objectives. Although unilateral hearing loss (UHL) has been proven to be associated with educational and behavioral problems, few studies have investigated psychopathological abnormalities in this population. The aim of this study was to evaluate the psychopathological influence of UHL among Korean 19-year-old males.Methods. The authors retrospectively compared the objective personality test profiles of 602 subjects with UHL with those of 23,790 peers with normal hearing. All participants in the current study were 19-year-old males who underwent a physical examination and completed the Korean Military Multiphasic Personality Inventory for conscription at the Military Manpower Administration from February 2015 to December 2016.Results. Significantly higher scores were found on neurosis scales in the UHL group than in the normal-hearing group (50.9± 10.8 vs. 44.9±6.0 for anxiety; 51.0±10.5 vs. 44.9±5.2 for depression; 51.1±10.4 vs. 45.1±6.81 for somatization, all PP

Objective For the proper treatment of first-episode psychosis, assessment of treatment response, remission, relapse, and recovery is important. Therefore, the present study aimed to develop operational definitions of clinical outcomes in first-episode psychosis.Methods A questionnaire was developed by a panel of experts and underwent three revisions. The final survey was presented to 150 psychiatrists who were members of the Korean Society for Schizophrenia Research. Respondents selected factors that they believed were important to consider while defining treatment response, remission, relapse, and recovery using a 6-point Likert scale. Selected factors that constituted each definition were statistically extracted, and operational definitions were developed.Results A total of 91 experts responded to the survey. The extent of reduction in psychopathology, socio-occupational functioning, and duration of each state were the core factors of each definition. Outcomes obtained from discussions and consultations by experts have been summarized and proposed.Conclusion The criteria developed in this survey tended to be somewhat stricter than those used by other studies. The fundamental reason for this is that this survey focused on first-episode psychosis. A better understanding of each definition in first-episode psychosis is necessary to improve effective treatment outcomes.

Objective Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC).Methods Twenty-four patients with schizophrenia and twelve HC underwent [18F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients.Results Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384).Conclusion Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.

Objectives. Dopamine receptor D2 gene (DRD2) and glucocorticoid receptor gene (NR3C1) are implicated in the development of psychosis. We investigated methylation levels of DRD2 and NR3C1 in peripheral blood of patients with recent-onset (RO) psychosis using bisulfite pyrosequencing as well as its association with childhood trauma and rumination. Methods. In all, 51 individuals with RO psychosis and 47 healthy controls were recruited. DNA methylation levels in the targeted regions of two genes were analyzed and compared. Childhood trauma and rumination were evaluated using the Early Trauma Inventory Self-Report Short Form (ETI-SF) and Brooding Scale (BS), respectively. Correlations between the scores of the ETI-SF and BS and methylation levels were explored. Results. For DRD2, we found no significant differences between groups in terms of methylation level or association with childhood trauma or rumination. For NR3C1, we found a trend level significance for average value of all CpG sites and significant hypermethylation or hypomethylation at specific sites. There was also a significant positive correlation between the methylation level at the CpG8 site of NR3C1 exon 1F and negative symptom subscale score of the PANSS (PANSS-N). Conclusion. Epigenetic alterations of NR3C1 are associated with the pathophysiology of psychosis. Further epigenetic studies will elucidate the molecular mechanisms underpinning the pathophysiology of psychosis.

Research on psychotic disorder not otherwise specified (PNOS) that clearly mentions its subgroups is very rare. This study was conducted to identify the demographic and clinical features, cognitive function, and 1-year outcomes of patients with early stage PNOS compared with those with early stage schizophrenia (SZ).The study subjects were 54 and 321 patients with PNOS and SZ, respectively, who were registered at least more than 1 year ago. Due to drop out, only 37 and 210 patients with PNOS and SZ were evaluated at the 1-year follow-up. We compared clinical variables (duration of untreated psychosis, symptom severity, self-rating scales, and so on), cognitive function, and short-term outcomes (treatment response, remission, compliance, drop out, relapse) between the two groups.The patients with PNOS were associated with higher diagnostic stability (53.7%) compared with those in previous studies. They had lower symptom severity, better treatment response at 2 months and higher remission rates at 12 months, but poorer compliance at 6 months compared with patients with SZ. Level of cognitive impairment in PNOS was intermediate between those of SZ patients and healthy controls.These findings indicate that PNOS has unique clinical features, suggesting that it should be treated as a distinct clinical syndrome. At the same time, however, prevention of its possible progression to other psychotic disorders in some patients with PNOS is also important.

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

Objective Metabolic side effects of antipsychotics significantly affect adherence to medication. We aimed to identify factors associated with the occurrence of metabolic diseases among Korean patients with schizophrenia (SCZ) from the national health insurance system database. We evaluated the frequency of antidiabetic and antihyperlipidemic use after diagnosis of SCZ according to typical or atypical antipsychotic use. Materials and methods Among the 43,800 patients diagnosed with SCZ between 2008 and 2012, 29,591 patients who had no metabolic diseases before the diagnosis were included in the analysis to investigate the occurrence of metabolic diseases associated with antipsychotic use. The associations between the development of metabolic diseases and patient characteristics were evaluated using logistic regression analysis. Results Use of both typical and atypical antipsychotics (multivariate-adjusted odds ratio (OR), 1.2513; 95% confidence interval (CI), 1.0953 - 1.4294) was associated with higher incidence of metabolic diseases than without their use. Among the atypical antipsychotics, use of clozapine (multivariate-adjusted OR, 1.1959; 95% CI, 1.0086 - 1.4179) and quetiapine (multivariate-adjusted OR, 1.1284; 95% CI, 1.0446 - 1.2189) showed higher incidence of metabolic diseases compared to that without their use. Among the patients using ≥ 1 type of antidiabetic or antihyperlipidemic agents within 6 years after diagnosis of SCZ, the proportion of patients using only atypical antipsychotics was greater than those using only typical antipsychotics. Conclusion The use of both typical and atypical antipsychotics, and clozapine and quetiapine treatment, may be associated with the occurrence of metabolic diseases in patients with SCZ. Additional prospective studies with accurate dosage information are needed to validate our findings.

BackgroundNetwork approach has been applied to a wide variety of psychiatric disorders. The aim of the present study was to identify network structures of remitters and non-remitters in patients with first-episode psychosis (FEP) at baseline and the 6-month follow-up.MethodsParticipants (n = 252) from the Korean Early Psychosis Study (KEPS) were enrolled. They were classified as remitters or non-remitters using Andreasen's criteria. We estimated network structure with 10 symptoms (three symptoms from the Positive and Negative Syndrome Scale, one depressive symptom, and six symptoms related to schema and rumination) as nodes using a Gaussian graphical model. Global and local network metrics were compared within and between the networks over time.ResultsGlobal network metrics did not differ between the remitters and non-remitters at baseline or 6 months. However, the network structure and nodal strengths associated with positive-self and positive-others scores changed significantly in the remitters over time. Unique central symptoms for remitters and non-remitters were cognitive brooding and negative-self, respectively. The correlation stability coefficients for nodal strength were within the acceptable range.ConclusionOur findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.

The classic subtype classification of schizophrenia has been removed, and DSM-5 now includes the Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). In the present study, a factor analysis of the CRDPSS was performed, and we assessed whether patient classification using the derived factor structure helps predict the clinical course. The participants were 390 patients with recent-onset psychosis enrolled in the Korean Early Psychosis Cohort Study (KEPS). Two factors were identified: psychotic (including delusions, hallucinations, disorganization, and abnormal psychomotor behavior) and negative-cognitive (including negative symptoms and impaired cognition). Patients were grouped based on the factor structure and changes in clinical course were monitored over 1 year. The negative-cognitive group demonstrated longer duration of untreated psychosis, earlier onset, and a higher rate of psychiatric comorbidities. Baseline Positive and Negative Syndrome Scale (PANSS) total and Clinical Global Impression-Severity (CGI-S) scores were higher in psychotic group, but group differences were not observed after 2 months. Conversely, the PANSS negative scale score was significantly higher in negative-cognitive group throughout follow-up, and CGI-S score was reversed at 12 months. The findings indicate that the factor structure derived herein for the CRDPSS could be helpful for predicting the clinical course of recent-onset psychosis patients.

Objectives Whilst reduced signalling and gene expression related to gamma-aminobutyric acid (GABA) play a role in the presumed pathophysiology of schizophrenia, its origin is unclear. Studying asymptomatic individuals with high genetic liability to schizophrenia (AIs) would provide insights. Therefore, this study aimed to investigate the role of genetic liability in GABAergic dysfunction of schizophrenia by exploring in vivo GABA-A/benzodiazepine receptor (GABAR) availability in AIs. Methods A total of 10 AIs with multiple relatives diagnosed as schizophrenia and 11 healthy controls underwent [11C]flumazenil positron emission tomography and neurocognitive function tests. Results There was no significant difference in [11C]flumazenil availability based on the groups. GABAR availability in caudate nuclei had positive correlations with genetic liability of AIs. GABAR availability in caudate nuclei and verbal memory measures of AIs revealed positive correlations. Only the correlation between right caudate and short-term verbal memory survived multiple-comparison correction (p = 0.030). Conclusions This study, for the first time, reports correlations between the genetic liability of schizophrenia and GABAR availability. Correlations between [11C]flumazenil binding in caudate of individuals with high genetic liability to schizophrenia suggests that the GABAergic dysfunction may arise from shared genetic factors and also that it may be responsible for cognitive impairment of AIs.

Objective The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations. Data sources MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019). Study selection The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations. Data extraction The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated. Results Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner. Conclusions The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

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.

OBJECTIVE This study aimed to examine the degree of clinical and functional improvement after paliperidone long-acting injectable (LAI) administration according to the duration of illness. METHODS Patients with schizophrenia diagnosed by ICD-10 criteria who were planned to start once-monthly paliperidone LAI were recruited from 2010 to 2017. Clinical and functional changes were measured every 4 weeks using the Clinical Global Impressions-Severity of Illness scale (CGI-S) and Personal and Social Performance scale (PSP), respectively, for 6 months after paliperidone LAI initiation. Improvements after starting paliperidone LAI were compared among patients with duration of illness < 3 years, ≥ 3 and < 10 years, and ≥ 10 years. RESULTS A total of 1,166 participants (duration of illness < 3 years, n = 240; 3 ≤ duration of illness < 10 years, n = 442; duration of illness ≥ 10 years, n = 484) were enrolled. The total olanzapine-equivalent doses of antipsychotics and the LAI monotherapy proportion at the final visit were significantly different among the 3 duration of illness groups (dose: F₂,₁₁₆₃ = 18.41, P < .001; monotherapy: χ²₂ = 11.73, P = .003). The changes in CGI-S score were significantly different according to the duration of illness, and those with duration of illness < 3 years showed the best improvement (group × week: χ²₁₂ = 25.33, P = .013). All 3 groups showed significantly improved PSP scores (week: χ²₆ = 294.2, P < .001). CONCLUSIONS Starting paliperidone LAI significantly improved clinical and functional outcomes in patients with schizophrenia, especially those with shorter duration of illness. These findings suggest that LAI antipsychotic administration may be considered in early-stage schizophrenia for improved outcomes.

Background The Seoul Pluripotent Risk for Mental Illness (SPRIM) study was designed to identify predictors leading to mental illness in help-seeking individuals by securing sufficient statistical power through transdiagnostic approaches. The SPRIM study aims to examine the clinical characteristics of high-risk individuals for mental illness and to identify proteomic biomarkers that can predict the onset of mental illness. Methods This paper describes the study protocol of the SPRIM study. We aim to recruit 150 participants who meet the criteria for high risk for major mental illness, 150 patients with major psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder), and 50 matched healthy control subjects for 2 years. Clinical evaluations, self-report measures, and proteomic analyses will be implemented. The assessment points are at baseline, 6, 12, 18, and 24 months. Conclusions In the present study, we introduced the study protocol of the SPRIM study, which is the first prospective cohort study of transdiagnostic high-risk concepts using proteomic biomarkers. This study has a paradigm that encompasses various diseases without aiming at predicting and preventing the development of a specific mental illness in help-seeking individuals. The transdiagnostic high-risk concept could be extended to provide a perspective for people with various psychopathological tendencies below a threshold, such that they do not meet the existing diagnostic criteria of mental illnesses, to determine what may lead them to a specific disease and help identify appropriate preventative interventions.

Background Rumination is a well-known risk factor for depression. It is also associated with negative and positive symptoms and suicidality in patients suffering from psychosis. However, no studies have addressed the effect of antipsychotics on rumination. Methods Using the Brooding Scale (BS), we investigated the effect of antipsychotics on rumination at the 6-month follow up in patients with first-episode psychosis (n = 257). The relationship between rumination and other clinical variables was explored by conducting a correlation analysis and structural equation modeling (SEM). The clinical characteristics and short-term outcomes were compared between high and low ruminators at 6 months. Results Significant reductions in rumination and various clinical variables were observed at the 6-month follow-up. A significant correlation was observed between rumination and the score on the positive subscale of the Positive and Negative Syndrome Scale (PANSS). A direct path between the PANSS score and rumination was identified by SEM. High ruminators had more severe psychopathology, experienced more childhood traumas, and took less exercise than low ruminators. The recovery rate at 6 months was higher in low ruminators than in high ruminators. Conclusions Our findings suggest that antipsychotics are beneficial for reducing rumination in patients with first-episode psychosis. The outcomes at the 6-month follow-up were better in low ruminators than high ruminators.

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as K

Several studies have investigated childhood trauma (ChT) and suicidality in psychosis. However, psychological factors intervening between ChT and suicidality are not well understood. The aims of this study were to explore the roles of negative schema and rumination in the relationship between ChT and suicidality in first-episode psychosis (FEP). Participants were 306 patients with FEP who were enrolled in the Korean Early Psychosis Cohort Study, a prospective naturalistic observational cohort study. ChT, suicidality, negative schema, and rumination were evaluated using the Early Trauma Inventory Self Report-Short Form, Columbia Suicide Severity Rating Scale, Brief Core Schema Scale, and Brooding Scale. In addition, psychopathology and depression were evaluated. Structural equation model and a phantom approach were employed to analyze the pathway from ChT to suicidality. We found close associations between ChT, rumination, negative schema, and suicidality. Importantly, negative schema played a direct intervening role in the relationship between ChT and suicidality in patients with FEP. Our findings suggest that targeting negative schema in individuals with FEP exposed to ChT will be an effective strategy for reducing suicidality.

BackgroundObsession and delusion are theoretically distinct from each other in terms of reality testing. Despite such phenomenological distinction, no extant studies have examined the identification of common and distinct neural correlates of obsession and delusion by employing biologically grounded methods. Here, we investigated dimensional effects of obsession and delusion spanning across the traditional diagnostic boundaries reflected upon the resting-state functional connectivity (RSFC) using connectome-wide association studies (CWAS).MethodsOur study sample comprised of 96 patients with obsessive–compulsive disorder, 75 patients with schizophrenia, and 65 healthy controls. A connectome-wide analysis was conducted to examine the relationship between obsession and delusion severity and RFSC using multivariate distance-based matrix regression.ResultsObsession was associated with the supplementary motor area, precentral gyrus, and superior parietal lobule, while delusion was associated with the precuneus. Follow-up seed-based RSFC and modularity analyses revealed that obsession was related to aberrant inter-network connectivity strength. Additional inter-network analyses demonstrated the association between obsession severity and inter-network connectivity between the frontoparietal control network and the dorsal attention network.ConclusionsOur CWAS study based on the Research Domain Criteria (RDoC) provides novel evidence for the circuit-level functional dysconnectivity associated with obsession and delusion severity across diagnostic boundaries. Further refinement and accumulation of biomarkers from studies embedded within the RDoC framework would provide useful information in treating individuals who have some obsession or delusion symptoms but cannot be identified by the category of clinical symptoms alone.

BackgroundGiven that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.MethodsTwenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.ResultsNo significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.ConclusionsThe relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.

Aripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.

Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects of delta-9-tetrahydrocannabinol (delta-9-THC), the main psychoactive ingredient of cannabis, on anxiety and on amygdala response while processing fearful stimuli were related to local availability of its main central molecular target, cannabinoid-1 (CB1) receptors in man. Fourteen healthy males were studied with fMRI twice, one month apart, following an oral dose of either delta-9-THC (10 mg) or placebo, while they performed a fear-processing task. Baseline availability of the CB1 receptor was studied using PET with [11C]MePPEP, a CB1 inverse agonist radioligand. Relative to the placebo condition, delta-9-THC induced anxiety and modulated right amygdala activation while processing fear. Both these effects were positively correlated with CB1 receptor availability in the right amygdala. These results suggest that the acute effects of cannabis on anxiety in males are mediated by the modulation of amygdalar function by delta-9-THC and the extent of these effects are related to local availability of CB1 receptors.

Background Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia pathophysiology, which underlies in majority of treatment-responsive patients. Although supported by findings that prefrontal cortical lesions lead to striatal dopamine dysregulation and that recently, prefrontal structural volume is negatively correlated with striatal dopamine synthesis, the relationship between corticostriatal connectivity and striatal dopamine synthesis has not been tested in patients with schizophrenia. We therefore investigated the relationship between corticostriatal connectivity and striatal dopamine synthesis capacity in treatment-responsive patients with schizophrenia, and compared them to treatment-resistant patients and healthy control subjects. Methods Twenty-four patients with schizophrenia and twelve matched healthy control subjects underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer), structural and diffusion 3T MRI. Connectivity(indexed as Fractional anisotropy, FA) were assessed in 3 major corticostriatal tracts (dorsolateral prefrontal cortex-associative striatum, ventromedial prefrontal cortex-limbic striatum, and pre/primary motor cortex-sensorimotor striatum). Furthermore, these measures were tested whether they were correlated with a measure of Wisconsin Card Sorting Test (WCST). Results Treatment responsive patients showed a negative correlation between connectivity of dorsolateral prefrontal cortex-associative striatum and striatal dopamine synthesis capacity of associative striatum, but this was not evident in treatment-resistant patients. Furthermore, WCST negatively correlated with Kicer in associative striatum and positively correlated with FA in dorsolateral prefrontal cortex-associative striatum in whole subjects and treatment responsive patients but not in treatment-resistant patients. Discussion These findings demonstrate that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia and especially, connectivity of dorsolateral prefrontal cortex-associative striatum is a core part for the different pathophysiology.

The objective of this study was to examine the extent of possible dissociation in pharmacokinetic decay between central dopamine D₂ receptor occupancy with antipsychotics and their peripheral blood concentrations.MEDLINE and Embase were searched using the following keywords: (positron emission tomography OR PET OR single-photon emission computed tomography OR SPECT) AND (dopamine OR D2) AND (receptor* OR occupanc*) AND antipsychotic*, with a limitation of English language (last search: December 14, 2019).The search identified 18 studies that met the following criteria: (1) including patients with schizophrenia spectrum disorders and/or healthy subjects, (2) using positron emission tomography or single-photon emission computed tomography, and (3) examining the time courses of D₂ occupancy with antipsychotics and their blood concentrations.The ratios of D₂ occupancy reduction rate (%) from peak to blood concentration reduction rate (%) from peak (relative attenuation ratio) were calculated.Among the studies, oral risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perospirone, haloperidol, sulpiride, and clozapine and long-acting injectable risperidone and haloperidol were included. Relative attenuation ratios were less than 1, indicating a slower central versus peripheral attenuation, across the time points for all antipsychotic types and doses with only a few exceptions. The ratio decreased in a dose-dependent as well as a peak D₂ occupancy-dependent fashion. It contrarily increased in a time-dependent manner.The findings indicate pharmacokinetic attenuation of antipsychotics was generally slower at the central versus the peripheral level and pose a critical challenge to the current dosing strategy that primarily relies on peripheral pharmacokinetics of antipsychotics.

Patients with schizophrenia are characterized by deficits in their ability to identify facial expressions of emotion, which are associated with impaired social and occupational function. An understanding of the deficits of facial affect recognition (FAR) early in the course of the illness can improve early intervention efforts to ameliorate potential functional deterioration. This study aimed to investigate the characteristics and correlations between psychotic symptoms and FAR deficits in patients with early-stage schizophrenia using data from the Korean Early Psychosis Cohort Study. Patients with schizophrenia were divided into three groups: 1) severely and markedly ill (n = 112), 2) moderately ill (n = 96), and 3) mildly ill (n = 115). These groups were compared with age- and sex-matched healthy controls. The FAR test was developed using Korean emotional faces from the Korean Facial Expressions of Emotion database. Error rates, correct response times, and nonresponse rates of each subset were calculated. Several psychopathology assessments were also performed. There were significantly more deficits associated with the recognition of anger (p < 0.01), fear (p < 0.01), and contempt (p < 0.01) in the three patient groups than in the healthy control group. In the severely and markedly ill states, all emotions apart from surprise had impaired error rates (p < 0.01 for all analyses). The error rates for happiness, sadness, disgust, surprise, and neutral faces were not significantly different between mildly ill patients and healthy controls. All emotions, except for sadness, had significantly more delayed correct response times in all patient groups than in the healthy controls (p < 0.01 for all analyses). The severity of psychotic symptoms was positively correlated with the happiness and neutral error rates, and depression was positively correlated with the happiness error rates. General social function was negatively correlated with the error rates for happiness, sadness, fear, disgust, and surprise. Overall, our results show that the severity of psychosis and clinical symptoms leads to distinct differences in certain emotions of patients with early-stage schizophrenia. It is considered that these specific emotional characteristics will help deepen our understanding of schizophrenia and contribute to early intervention and recovery of social function in patients with schizophrenia.

Objective High rates of childhood trauma and adult suicidality have been reported in patients who have schizophrenia. This study sought to explore mediators between childhood trauma and suicidality in adulthood to help determine therapeutic approaches. Methods This study included 314 adult patients with early psychosis who were participants in the Korean Early Psychosis Cohort Study, which was a prospective naturalistic observational cohort study started in December 2014. DSM-5 criteria were used to assign the diagnosis of schizophrenia spectrum and other psychotic disorders. Cross-sectional data obtained at baseline were used for analysis. The Early Trauma Inventory Self Report-Short Form and the Columbia Suicide Severity Rating Scale were employed to collect data on childhood trauma and suicidal ideation and attempts. Other measures were used to evaluate depression, empathy, psychopathology, and rumination. Results A total of 90.1% of the participants experienced at least 1 childhood traumatic event. The rates of significant` physical punishment, emotional abuse, and sexual events were 37.3%, 35.6%, and 6.4%, respectively. The rates of recent suicidal ideation and attempts were 32.0% and 10.0%, respectively. Independent predictors of recent suicidal ideation included depression, negative schema, and rumination. Furthermore, negative schema and rumination played partial or full mediating roles in the relationship between childhood trauma and recent suicidal ideation. Conclusions These findings highlight the importance of performing careful evaluations of childhood trauma and suicidality and of developing effective strategies to reduce mediating factors that may be amenable to psychosocial approaches.

Some patients with schizophrenia show poor response to first-line antipsychotic treatments and this is termed treatment resistant schizophrenia. The differential response to first-line antipsychotic drugs may reflect a different underlying neurobiology. Indeed, a previous study found dopamine synthesis capacity was significantly lower in patients with treatment resistant schizophrenia. However, in this study, the treatment resistant patients were highly symptomatic whilst the responsive patients showed no or minimal symptoms. The study could not distinguish whether this was a trait effect or reflected the difference in symptom levels. Thus we aimed to test whether dopaminergic function is altered in patients with a history of treatment resistance to first-line drugs relative to treatment responders when both groups are matched for symptom severity levels by recruiting treatment resistant patients currently showed low symptom severity with the clozapine treatment. Healthy controls(n=12), patients treated with clozapine(n=12) who had not responded to first-line antipsychotics and patients who had responded to first-line antipsychotics(n=12) were recruited. Participants were matched for age and sex, and symptomatic severity level in patient groups. Participants' dopamine synthesis capacity was measured by using [(18)F]DOPA PET. We found that patients treated with clozapine show lower dopamine synthesis capacity than patients who have responded to first-line treatment(Cohen's d=0.9191(whole striatum), 0.7781(Associative striatum), 1.0344(Limbic striatum), 1.0189(Sensorimotor striatum) in line with the hypothesis that the dopaminergic function is linked to treatment response. This suggests that a different neurobiology may underlie treatment resistant schizophrenia and that dopamine synthesis capacity may be a useful biomarker to predict treatment responsiveness.Neuropsychopharmacology accepted article preview online, 18 November 2016. doi:10.1038/npp.2016.258.

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.

Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine.Twenty-four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans.No significant difference was found in the total PANSS score between the patient groups. Voxel-based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups.The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not.