Understanding the Fluctuations in Korea's Suicide Rates: A Change-Point Analysis and Interrupted Time Series Analysis.

BACKGROUND: Korea has witnessed significant fluctuations in its suicide rates in recent decades, which may be related to modifications in its death registration system. This study aimed to explore the structural shifts in suicide trends, as well as accidental and ill-defined deaths in Korea, and to analyze the patterns of these changes. METHODS: We analyzed age-adjusted death rates for suicides, deaths due to transport accidents, falls, drowning, fire-related incidents, poisonings, other external causes, and ill-defined deaths in Korea from 1997 to 2021. We identified change-points using the 'breakpoints' function from the 'strucchange' package and conducted interrupted time series analyses to assess trends before and after these change-points. RESULTS: Korea's suicide rates had three change-points in February 2003, September 2008, and June 2012, characterized by stair-step changes, with level jumps at the 2003 and 2008 change-points and a sharp decline at the 2012 change-point. Notably, the 2003 and 2008 spikes roughly coincided with modifications to the death ascertainment process. The trend in suicide rates showed a downward slope within the 2003-2008 and 2008-2012 periods. Furthermore, ill-defined deaths and most accidental deaths decreased rapidly through several change-points in the early and mid-2000s. CONCLUSION: The marked fluctuations in Korea's suicide rate during the 2000s may be largely attributed to improvements in suicide classification, with potential implications beyond socio-economic factors. These findings suggest that the actual prevalence of suicides in Korea in the 2000s might have been considerably higher than officially reported.

Trends in suicide deaths before and after the COVID-19 outbreak in Korea.

We investigated the effect of the coronavirus disease-2019 (COVID-19) pandemic on suicide trends in Korea via a time-series analysis. We used Facebook Prophet to generate forecasting models based on the monthly numbers of suicide deaths in Korea between 1997 and 2018, validated the models by comparison with the 2019 numbers, and predicted the numbers of suicides in 2020. We compared the expected and observed numbers of suicides during the COVID-19 pandemic. The total numbers of suicides during the COVID-19 pandemic did not deviate from projections based on the pre-pandemic period. However, the number of suicides among women and those under the age of 34 years significantly exceeded the expected level. The COVID-19 pandemic did not increase the overall suicide rate significantly. However, suicides among women and young people increased, suggesting that the pandemic might drive more members of these groups to suicide. Further studies are needed to verify the long-term impact of the COVID-19 pandemic on suicide.

Changing Seasonal Pattern of Suicides in Korea Between 2000 and 2019.

OBJECTIVE: This study aimed to investigate the changing seasonal pattern of suicides in Korea between 2000 and 2019. METHODS: We calculated a seasonal pattern of suicides between 2000 and 2019 using a non-stationary cosinor model. In addition, we estimated the effect of each month on the suicide incidence compared to a reference month, using a generalized linear model with a categorical variable of the month. Then, we visualized the rate ratio curves of suicides by gender, age group, and subperiod. RESULTS: We observed a seasonal pattern of suicides in Korea with a spring peak and a winter trough. The seasonal ups and downs were most pronounced in suicides among the elderly ≥65 years. However, the seasonal pattern has not been consistent over the past two decades, with lowering seasonal peaks since 2012. The amplitude of seasonality was also lower in 2010-2019 than in 2000-2009. CONCLUSION: The seasonal pattern of suicides seems to have diminished in Korea in recent years. Thus, we need further studies to investigate climatic and non-climatic factors influencing the seasonality of suicides and the consequence of the change.

Decline in Hospital Visits by Patients with Schizophrenia Early in the COVID-19 Outbreak in Korea.

OBJECTIVE: This study investigated trends in hospital utilization by patients with schizophrenia during the first wave of the COVID-19 outbreak in Korea. METHODS: The Prophet algorithm was used to predict the monthly number of patients with schizophrenia in 2020 based on medical insurance data between 2010 and 2019. The projected expectations were compared with the actual number of patients receiving outpatient and inpatient treatment each month in the first half of 2020. We conduct interrupted time series analyses of short-term data to determine the significance of recent changes in the trend of hospital visits by patients with schizophrenia. RESULTS: The prediction model showed that the actual number of patients receiving treatment each month during the early COVID-19 outbreak decreased by up to 3.6% compared to the projected expectations. The interrupted time series model also revealed a significant change in hospital utilization compared to the year before the onset of COVID-19 in Korea (F = 8.961, p = 0.010). CONCLUSION: This suggests that many patients with schizophrenia were not receiving adequate treatment during the COVID-19 outbreak. A strategy should be developed to keep treating patients with schizophrenia during the COVID-19 pandemic.

Current and Future Trends in Hospital Utilization of Patients With Schizophrenia in Korea: A Time Series Analysis Using National Health Insurance Data.

OBJECTIVE: This study aimed to investigate trends in hospital utilization of patients with schizophrenia during the last 10 years in Korea and to predict future trends using time series analysis. METHODS: We determined the numbers of patients receiving outpatient or inpatient treatment for schizophrenia per month between 2010 and 2019, using National Health Insurance claims data. Facebook's Prophet was used to fit time series models based on observations for the previous 120 months, and to predict trends over the next 36 months. RESULTS: The number of hospitalized patients per month has declined rapidly since 2015, but the monthly number of outpatient visits has steadily increased. Monthly hospital utilization has increased in patients aged ≤29 and ≥50 years, but has declined rapidly since 2014-2015 in patients in their 30s and 40s. The upward trend in overall hospital utilization has slowed considerably in recent years. These trends are expected to continue over the next few years. CONCLUSION: This study revealed some notable changes in the hospital utilization patterns of patients with schizophrenia in recent years. There is a need to closely monitor and anticipate potential problems caused by these changing trends.

The Psychology of Food Cravings in Patients With First-Episode Psychosis.

Objectives: Food cravings may cause weight gain in patients with schizophrenia. This study investigated psychological characteristics associated with food cravings in patients with first-episode psychosis. Methods: This study analyzed data from a clinical cohort of first-episode psychosis patients taking antipsychotics for 3 months or less. The strength of food cravings was measured using the General Food Cravings Questionnaire-Trait (G-FCQ-T). Psychological characteristics and psychiatric symptoms were investigated with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Assessment Scale, Rosenberg Self-Esteem Scale (RSES), and Perceived Stress Scale (PSS). Clinical characteristics were compared according to significant weight gain (≥10% increase in body weight compared to baseline) over 3 months. Associations between the G-FCQ-T and other psychiatric scales were investigated. We conducted sex-stratified analyses. Results: In total, 182 patients (78 males and 104 females) with first-episode psychosis were enrolled in this study. In females, the G-FCQ-T total score at baseline was associated with baseline body weight and significant weight gain over 3 months. The PSS scales were significantly associated the G-FCQ-T total and all subscale scores in female participants. Scores on the RSES and CDSS were significantly associated with the G-FCQ-T total score and with the preoccupation and loss of control subscale scores. The PANSS negative and general subscales were significantly associated with the positive outcome expectancy and loss of control subscales of the G-FCQ-T, respectively. In males, the only significant association was between the loss of control subscale and RSES scores. Linear regression analysis showed significant associations of PSS scores with the total and all subscale scores of the G-FCQ-T despite the loss of significance for other variables. Conclusion: These results indicate that the food cravings in patients with first-episode psychosis, which were associated with weight gain, were influenced by perceived stress in females. To reduce food cravings in female patients with schizophrenia, interventions aimed at perceived stress should be considered.

Network Structures of Social Functioning Domains in Schizophrenia and Bipolar Disorder: A Preliminary Study.

OBJECTIVE: : This study used network analyses to examine network structures reflecting interactions between specific domains of social functioning in schizophrenia (SZ) and bipolar disorder (BD). METHODS: We used the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) to assess six domains of social functioning ('cognition', 'mobility', 'self-care', 'getting along', 'life activities', and 'participation') in 143 patients with SZ, 81 patients with BD, and 106 healthy subjects. We constructed regularized partial correlation networks, estimated network centrality and edge strength, tested network stability, and compared SZ and BD network structures. RESULTS: Patients with SZ showed a significantly higher level of functional disability than patients with BD. In the networks we constructed, 'cognition' was the most central domain of social functioning in both SZ and BD. The 'cognition' domain was primarily associated with the 'getting along' domain in the SZ network and the 'life activities' domain in the BD network. We found no significant group-level differences in network structures for SZ vs. BD. CONCLUSION: Our results suggest that cognition may play a pivotal role in social functioning in both SZ and BD. In addition, domains of social functioning in SZ and BD have similar network structures despite the higher level of disability in SZ compared to BD.

Prevalence of Metabolic Syndrome in Patients with Schizophrenia in Korea: A Multicenter Nationwide Cross-Sectional Study.

OBJECTIVE: We designed a nationwide study with limited exclusion criteria to investigate the prevalence of metabolic syndrome (MetS) in Korea and its relationship with antipsychotic medications. METHODS: This multicenter, cross-sectional, and observational study included patients diagnosed with schizophrenia or schizoaffective disorder. Sixteen hospitals enrolled 845 patients aged 18 to 65 years prescribed any antipsychotic medication between August 2011 and August 2013. MetS was diagnosed using the criteria of the modified Adult Treatment Panel III of the National Cholesterol Education Program with the Korean abdominal obesity definition (waist circumference ≥85 cm in women, ≥90 cm in men). RESULTS: The prevalence of MetS in all patients was 36.5% and was significantly higher in men than women (men, 40.8%; women, 32.2%) and was significantly correlated with age [odds ratio (OR) 1.02] and duration of illness (OR 1.03). The prevalence of MetS across antipsychotic drugs in the major monotherapy group was as follows: 18.8% for quetiapine, 22.0% for aripiprazole, 33.3% for both amisulpride and paliperidone, 34.0% for olanzapine, 35% for risperidone, 39.4% for haloperidol, and 44.7% for clozapine. CONCLUSION: The prevalence of MetS is very high in patients with schizophrenia or schizoaffective disorder. Screening and monitoring of MetS is also strongly recommended.

Suppression of Heme Oxygenase-1 by Prostaglandin E2-Protein Kinase A-A-Kinase Anchoring Protein Signaling Is Central for Augmented Cyclooxygenase-2 Expression in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

PURPOSE: Prostaglandin (PG) E2 is an immunomodulatory lipid mediator generated mainly via the cyclooxygenase-2 (COX-2) pathway from arachidonic acid at sites of infection and inflammation. A positive feedback loop of PGE2 on COX-2 expression is critical for homeostasis during toll-like receptor (TLR)-mediated inflammatory processes. The mechanism of PGE2-regulated COX-2 expression remains poorly understood. The low-molecular-weight stress protein heme oxygenase-1 (HO-1) contributes to the anti-inflammatory, anti-oxidant and anti-apoptotic response against environmental stress. METHODS: We explored the involvement of HO-1 on PGE2 regulation of LPS-induced COX-2 expression in RAW 264.7 macrophages. RESULTS: LPS-induced COX-2 expression in RAW 264.7 macrophages was enhanced by exogenous PGE2 or cyclic AMP (cAMP) analogue and was suppressed by a COX inhibitor (indomethacin), a protein kinase A (PKA) inhibitor (KT5720), and A kinase anchoring protein (AKAP) disruptors (Ht31 and RIAD). This result suggests that the stimulatory effects of endogenous and exogenous PGE2 on COX-2 expression are mediated by a cAMP-PKA-AKAP-dependent pathway. The induction of HO-1 was observed in LPS-stimulated RAW 264.7 macrophages. This induction was suppressed by exogenous PGE2 and enhanced by blockage of the endogenous PGE2 effect by the PKA inhibitor or AKAP disruptors. In addition, HO-1 induction by the HO activator copper protoporphyrin suppressed LPS-induced COX-2 expression, which was restored by the addition of exogenous PGE2. The induction of HO-1 inhibited LPS-induced NF-kappaB p-65 nuclear expression and translocation. CONCLUSIONS: AKAP plays an important role in PGE2 regulation of COX-2 expression, and the suppression of HO-1 by PGE2-cAMP-PKA-AKAP signaling helps potentiate the LPS-induced COX-2 expression through a positive feedback loop in RAW 264.7 macrophages.

Symptom structure of antipsychotic-induced obsessive compulsive symptoms in schizophrenia patients.

OBJECTIVE: The use of clozapine or other second generation antipsychotics (SGAs) has been reported to produce obsessive compulsive (OC) symptoms as adverse mental affects. However, it is not yet clear if SGA-induced OC symptoms have the same phenomenological characteristics as those displayed in obsessive compulsive disorder (OCD). This study investigated the nature of symptoms and dimensions of SGA-induced OC symptoms in schizophrenia patients, which were then compared with those reported in pure OCD. METHODS: The study subjects were fifty-one schizophrenia patients with SGA-induced OC symptoms. Symptom evaluation was performed using the Korean version of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Exploratory factor analysis of symptom categories of Y-BOCS symptom checklist (Y-BOCS-SC) was conducted. RESULTS: Frequencies of individual symptom categories were comparable to those reported in Korean OCD patients. Five factors (forbidden thoughts, hoarding, cleaning, symmetry, and counting) were generated from 13 main symptom categories, which accounted for 70.7% of the total variance. This factor structure is also remarkably similar to those reported in pure OCD patients. The factor score of 'cleaning' was significantly correlated with the overall severity of OC symptoms (P<0.01). CONCLUSION: A high level of similarity between the nature of symptoms and dimensions identified in patients with SGA-induced OC symptoms and those revealed in OCD patients suggests a common biological mechanism underlying these two clinical conditions.

Interaction between genetic variants of DLGAP3 and SLC1A1 affecting the risk of atypical antipsychotics-induced obsessive-compulsive symptoms.

Adverse effects of atypical antipsychotics (AAP) can include obsessive-compulsive (OC) symptoms. Based on biological evidence of the relationship between the glutamatergic system and both OC disorder and AAP, this study aimed to determine whether DLGAP3, coding a post-synaptic scaffolding protein of glutamatergic synapses, is associated with AAP-induced OC symptoms. Furthermore, we explored the interactions between DLGAP3 and a previously reported susceptibility gene, the glutamate transporter gene SLC1A1, regarding this phenotype. Subjects were clinically stable schizophrenia patients receiving AAP treatment (n = 94), and they comprised an OC group (n = 40) and a non-OC group (n = 54) (patients with and without AAP-induced OC symptoms, respectively). We performed allelic/genotypic/haplotype association analyses for seven tag single-nucleotide polymorphisms of DLGAP3 and gene-gene interaction analyses with rs2228622 of SLC1A1, observing a nominally significant association between AAP-induced OC symptoms and rs7525948 in both simple chi-square tests and the regression analyses (nominal P < 0.05). In the logistic regression analysis of gene-gene interaction, we found a significant interaction effect of rs7525948 of DLGAP3 and rs2228622 of SLC1A1 (permutation P = 0.036) on AAP-induced OC symptoms, with a 30.2 times higher odds for individuals carrying risk genotypes at both loci in comparison with the reference group, which had no risk genotypes. This study provides suggestive evidence that DLGAP3 and its interactive effect with SLC1A1 might be involved in susceptibility to developing OC symptoms in schizophrenia patients receiving AAP treatment.

Factor structure of the neurocognitive tests: an application of the confirmative factor analysis in stabilized schizophrenia patients.

The purpose of the present study was to identify the factor structure of neurocognitive tests used on schizophrenia patients by using the confirmative factor analysis, and to assess the factor score differences of schizophrenia patients and healthy controls. Comprehensive neurocognitive tests were administered to stabilized schizophrenia patients (N=114) and healthy controls (N=120). In the results of factor analyses on patients, the multifactorial-6-factor model, which included the speed of processing, working memory, verbal learning and memory, visual learning and memory, attention/vigilance, and reasoning/problem solving as suggested by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS), showed the better goodness of fit than any of the other models tested. And assessing the group differences of factor scores, we found the patients performed worse than the controls in all factors, but the result showed meaningful variations of impairments across the cognitive factors. Our study identifies the six major domains with multifactorial structure of cognitive abilities in schizophrenia patients and confirms the distinctive impairment patterns of each cognitive domain. These results may have utility in better understanding the pathology of schizophrenia as well as in genetic studies.

Association of the glutamate transporter gene SLC1A1 with atypical antipsychotics-induced obsessive-compulsive symptoms.

CONTEXT: Several studies have indicated that atypical antipsychotics (AAP) induce obsessive-compulsive (OC) symptoms. Research exploring the mechanism of this phenomenon, however, has been extremely limited. Considering the indirect evidence of genetic control and difficulties in developing animal models and performing gene expression studies, genetic association studies could be an important approach to understanding the molecular mechanism of AAP-induced OC symptoms. The glutamate transporter gene SLC1A1, which was recently reported to be associated with obsessive-compulsive disorder (OCD), is a promising candidate gene for susceptibility to AAP-induced OC symptoms. OBJECTIVE: To determine whether polymorphisms in SLC1A1 are associated with AAP-induced OC symptoms in patients with schizophrenia. DESIGN: A pharmacogenetic case-control association study. SETTING: Outpatient schizophrenia clinics. PATIENTS: Clinically stable patients with schizophrenia who were receiving AAP treatment (n = 94; OC group). The OC group consisted of 40 patients with AAP-induced OC symptoms, and the non-OC group consisted of 54 patients who had received AAP for more than 24 months without developing OC symptoms. MAIN OUTCOME MEASURES: Allele, genotype, and haplotype frequencies. The association was tested with a logistic regression model using age, sex, and medication type as covariates. RESULTS: Trends of association were observed in rs2228622 and rs3780412 (nominal P = .01; adjusted permutation P = .07) for the dominant model that was the inheritance model that best fit our data. In the haplotype -based analysis, the A/C/G haplotype at rs2228622-rs3780413-rs3780412 showed a significant association with AAP-induced OC symptoms; this association withstood multiple test correction (nominal P = .01; adjusted permutation P = .04; odds ratio, 3.955; 95% confidence interval, 1.366-11.452, for dominant model). CONCLUSIONS: These results suggest that sequence variations in SLC1A1 are associated with susceptibility to AAP-induced OC symptoms. This is the first published pharmacogenetic study on this phenomenon and provides preliminary evidence of the involvement of glutamatergic neurotransmission in the pathogenesis of AAP-induced OC symptoms.

Determination of pharmacokinetic properties of clozapine and norclozapine in Korean schizophrenia patients.

There is a wide interethnic variance in the pharmacokinetic profile of clozapine (CLZ), but the accumulated data are limited to some regional populations. In this study, we investigated the pharmacokinetic profile of CLZ in Korean patients and examined the association between serum CLZ parameters and clinical outcome. We assessed 78 Korean patients with schizophrenia who had been taking CLZ medication for more than 6 months. The patients were classified into three groups (good, moderate, and poor responders) according to their Clinical Global Impressions-Improvement scores. The serum concentrations of CLZ and norclozapine were 610.7+/-368.4 and 314.5+/-163.0 ng/ml (mean+/-SD), respectively, showing a large interindividual variation that was affected by dose, age, smoking habits, and sex by variable degrees. The pharmacokinetic profiles of Koreans were similar to those observed in Asians but quite different from those in Caucasians. Investigation on clinical responses revealed that the good or moderate responders clinically improved at a relatively low serum CLZ levels, whereas the poor responders showed less improvement despite the higher doses and serum levels. The metabolic ratio of the good responders was 0.65+/-0.20, higher than the poor responders (P=0.033). In this study, we identified a pharmacokinetic profile of CLZ in Korean schizophrenia patients and found a wide interindividual difference affected by various factors.

Cognitive profiles of healthy siblings of schizophrenia patients: application of the cognitive domains of the MATRICS consensus battery.

Even though a large body of data suggests the presence of various types of cognitive deficits in the unaffected relatives of schizophrenia patients, more study is needed to clarify the comparative sensitivities of specific cognitive measures for relative-control differences. In this study, the authors compared the cognitive profiles of unaffected siblings of schizophrenia patients and those of patients and normal controls, and attempted to identify cognitive markers that might be associated with genetic liability to schizophrenia. Eighty-eight clinically stable schizophrenia patients, 44 healthy patient siblings, and 100 normal controls were evaluated using comprehensive neuropsychological tests. The domain structure of the MATRICS consensus cognitive battery was adopted, and both domain scores and individual test scores were used in the analysis. Performances of the sibling group were intermediate between those of patients and controls on most measures. A significant difference between the sibling and control groups was observed only in the Category Fluency Test. This cognitive deficit might be caused by familial predisposition to schizophrenia and could be a candidate of endophenotype for schizophrenia.

In vitro activities of 28 antimicrobial agents against Staphylococcus aureus isolates from tertiary-care hospitals in Korea: a nationwide survey.

Staphylococcus aureus, one of the most frequently isolated pathogens in both hospitals and the community, has been particularly efficient at developing resistance to antimicrobial agents. As methicillin-resistant S. aureus (MRSA) has prevailed and, furthermore, as S. aureus with reduced susceptibility to vancomycin has emerged, the therapeutic options for the treatment of S. aureus infections have become limited. To update the current status of antibiotic resistance, clinical S. aureus isolates were collected from eight university-affiliated hospitals from June 1999 to January 2001. Susceptibility tests with 28 antibiotics were performed by the disk diffusion method. Among a total of 682 isolates, the methicillin resistance rate was 64% (439 of 682), and most of the MRSA isolates were resistant to multiple classes of antibiotics. Although a constitutive macrolide-lincosamide-streptogramin B resistance phenotype was common, no isolates were resistant to quinupristin-dalfopristin or linezolid. Rifampin, fusidic acid, trimethoprim-sulfamethoxazole, and arbekacin showed superior in vitro activity compared with the other antibiotics against the MRSA isolates. No isolates showed reduced susceptibility to vancomycin.

A virulent strain of Salmonella enterica serovar London isolated in infants with enteritis traced by active surveillance and molecular epidemiological study.

A total of 74 isolates of Salmonella enterica serovar London were collected through the Laboratory-Based Diarrheal Diseases Surveillance in 2000-2001. In order to characterize the isolates and investigate the source of the epidemic, we performed antimicrobial susceptibility tests and XbaI Pulsed-field gel electrophoresis (PFGE) of 44 Salmonella London isolates. Forty isolates were from feces of infants and four isolates were from adults aged 30, 52, 54, and 59 yr. Two subtypes were identified: a tetracycline-susceptible A 0 PFGE pattern and a tetracyclineresistant A 1 PFGE pattern. Interestingly, the isolates from all infants and one 30-yr-old adult were A 0 PFGE pattern and tetracycline-susceptible. Furthermore, the A 0 PFGE pattern strain was approximately 2 times more virulent than the A 1 PFGE pattern strain, according to the results of in vitro invasion assay using J774A.1 macrophage-like cells. These results indicate that the active surveillance with molecular epidemiological tools would be valuable for promptly finding new epidemic strains. Our results also suggested that the virulent Salmonella London strain might infect the infants through a common contaminated source.