Efficacy and Safety of Lurasidone vs. Quetiapine XR in Acutely Psychotic Patients With Schizophrenia in Korea: A Randomized, Double-Blind, Active-Controlled Trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of lurasidone (160 mg/day) compared to quetiapine XR (QXR; 600 mg/day) in the treatment of acutely psychotic patients with schizophrenia. METHODS: Patients were randomly assigned to 6 weeks of double-blind treatment with lurasidone 160 mg/day (n=105) or QXR 600 mg/day (n=105). Primary efficacy measure was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions severity (CGI-S) score. Adverse events, body measurements, and laboratory parameters were assessed. RESULTS: Lurasidone demonstrated non-inferiority to QXR on the PANSS total score. Adjusted mean±standard error change at week 6 on the PANSS total score was -26.42±2.02 and -27.33±2.01 in the lurasidone and QXR group, respectively. The mean difference score was -0.91 (95% confidence interval -6.35-4.53). The lurasidone group showed a greater reduction in PANSS total and negative subscale on week 1 and a greater reduction in end-point CGI-S score compared to the QXR group. Body weight, body mass index, and waist circumference in the lurasidone group were reduced, with significantly lower mean change compared to QXR. Endpoint changes in glucose, cholesterol, triglycerides, and low-density lipoprotein levels were also significantly lower. The most common adverse drug reactions with lurasidone were akathisia and nausea. CONCLUSION: Lurasidone 160 mg/day was found to be non-inferior to QXR 600 mg/day in the treatment of schizophrenia with comparable efficacy and tolerability. Adverse effects of lurasidone were generally tolerable, and beneficial effects on metabolic parameters can be expected.

The Mediating Role of Anxiety/Depression Between Auditory Verbal Hallucinations and the Level of Insight in Schizophrenia.

OBJECTIVE: Auditory verbal hallucination (AVH) is a prominent symptom of schizophrenia causing profound distress. The influence of AVHs on insight appears to be intricate and contingent on other accompanying symptoms. This study investigated the relationship and possible mediators between AVHs and the degree of insight. METHODS: One hundred patients with schizophrenia participated in the study. Scales were used to evaluate the hallucinatory experience, the level of insight and other psychopathology. Complex relationships between variables were envisaged as a path model, whose initial structure was constructed via Gaussian Graphical Model. The validity of the final model was verified by Structural Equation Modeling. Separate analyses were performed for self-reported and clinician-rated data to enhance the model's robustness. RESULTS: The greater the severity of the physical aspects of AVHs, the lower the level of insight observed. Conversely, higher emotional distress was associated with increased insight. These relationships were only evident in the self-reported results and were not reflected in the clinician-rated results. The path model suggested that the Positive and Negative Syndrome Scale (PANSS) anxiety/depression factor was an important mediator that linked the found association. Notably, the PANSS negative symptom had the opposite effect on the PANSS anxiety/depression factor and insight, making it difficult to define its overall effect. CONCLUSION: The findings of this study provided one possible route for the positive influence of AVH experience in gaining insight. The mediating role of anxiety/depression modified by negative symptoms emerged as a valuable concept for clarifying this intricate relationship.

Change in absolute neutrophil count after COVID-19 infection in patients using clozapine versus other antipsychotics.

It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P  = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs.

Effects of Long-acting Injectable 3-Monthly Paliperidone Palmitate on the Clinical and Social Performance of Patients with Schizophrenia.

Objective: To investigate the effects of long-acting injectable 3-monthly paliperidone palmitate on the clinical and social functioning of patients with schizophrenia. Methods: This study enrolled patients with schizophrenia receiving long-acting injectable 1-monthly paliperidone palmitate for at least 4 months and who subsequently received 3-monthly paliperidone palmitate. Accordingly, 418 patients were followed up for 24 weeks. Their clinical symptoms and social functioning were measured using the Clinical Global Impression-Severity of Illness and Personal and Social Performance scales. Results: The Personal and Social Performance total score was significantly higher after 3-monthly paliperidone palmitate treatment than at baseline (baseline vs. week 24: 54.3 ± 18.0 vs. 61.0 ± 14.5 [mean ± standard deviation]; p < 0.001; Wilcoxon signed-rank test); the proportion of patients in the mildly ill group (scores 71-100) also increased significantly (baseline vs. week 24: 16.5% vs. 20.6%; p < 0.001; McNemar-Bowker test). The mean Clinical Global Impression-Severity of Illness score decreased significantly (baseline vs. week 24: 3.7 ± 1.0 vs. 3.4 ± 0.9; p < 0.001; Wilcoxon signed-rank test), as did the proportion of patients in the severely ill group (baseline vs. week 24: 4.1% vs. 2.1%; p < 0.001; McNemar-Bowker test). Conclusion: Continuous 3-monthly paliperidone palmitate treatment significantly enhances the personal and social performance of patients with schizophrenia and reduces the proportion of those with severe illness. These findings suggest that long-acting injectable antipsychotic administration at intervals longer than 1 month might improve the social functioning of and promote return to activities of daily living in patients with schizophrenia.

Resolution of Persistent Auditory Verbal Hallucinations after Long-term Electroconvulsive Therapy Maintenance: A Case Report of a Patient with Clozapine-resistant Schizophrenia.

A 32-year-old woman with schizophrenia and persistent auditory verbal hallucinations (AVHs), which caused continuous suicidal thoughts and depression, was treated with electroconvulsive therapy (ECT) of an acute course followed by maintenance ECT (M-ECT) augmented onto clozapine for 7 years. Although the general psychopathology and AVHs initially reduced slightly with ECT and clozapine, her AVHs and suicidal thoughts did not decrease subjectively. When 3 years of M-ECT, her voices declined sharply, and improvement was maintained for 2 years thereafter. A total 91 ECT sessions were performed. The daily clozapine dose was decreased from 325 to 200 mg and plasma levels remained higher than 350 ng/ml; there were no noticeable cognitive side effects. In summary, we report a case showing a sudden sharp reduction in persistent AVHs after 3 years of long-term M-ECT.

Recent Updates on Electro-Convulsive Therapy in Patients with Depression.

OBJECTIVE: Electro-convulsive therapy (ECT) has been established as a treatment modality for patients with treatment-resistant depression and with some specific subtypes of depression. This narrative review intends to provide psychiatrists with the latest findings on the use of ECT in depression, devided into total eight sub-topics. METHODS: We searched PubMed for English-language articles using combined keywords and tried to analyze journals published from 1995-2020. RESULTS: Pharmacotherapy such as antidepressants or maintenance ECT is more effective than a placebo as prevention of recurrence after ECT. The use of ECT in treatment-resistant depression, depressed patients with suicidal risks, elderly depression, bipolar depression, psychotic depression, and depression during pregnancy or postpartum have therapeutic benefits. As possible mechanisms of ECT, the role of neurotransmitters such as serotonin, dopamine, gamma-aminobutyric acid (GABA), and other findings in the field of neurophysiology, neuro-immunology, and neurogenesis are also supported. CONCLUSION: ECT is evolving toward reducing cognitive side effects and maximizing therapeutic effects. If robust evidence for ECT through randomized controlled studies are more established and the mechanism of ECT gets further clarified, the scope of its use in the treatment of depression will be more expanded in the future.

Initial Seizure Threshold in Brief-Pulse Bilateral Electroconvulsive Therapy in Patients with Schizophrenia or Schizoaffective Disorder.

OBJECTIVE: The present study aimed to report the initial seizure threshold (IST) of a brief-pulse bilateral electroconvulsive therapy (BP-BL ECT) in Korean patients with schizophrenia/schizoaffective disorder and to identify IST predictors. METHODS: Among 67 patients who received ECT and diagnosed with schizophrenia/schizoaffective disorder based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, we included 56 patients who received 1-millisecond BP-BL ECT after anesthesia with sodium thiopental between March 2012 and June 2018. Demographic and clinical information was gathered from electronic medical records, and a multiple regression analysis was conducted to identify predictors of the IST. RESULTS: The mean age of the patients was 36.9±12.0 years and 30 (53.6%) patients were male. The mean and median IST were 105.9±54.5 and 96 millicoulombs (mC), respectively. The IST was predicted by age, gender, and dose (mg/kg) of sodium thiopental. Other physical and clinical variables were not associated with the IST. CONCLUSION: The present study demonstrated that the IST of 1-ms BP-BL ECT following sodium thiopental anesthesia in Korean patients was comparable to those reported in previous literature. The IST was associated with age, gender, and dose of sodium thiopental.

Differences between self-reported and clinician-rated evaluations of 1-year changes in auditory verbal hallucinations among schizophrenia patients.

Auditory verbal hallucinations (AVHs) constitute a frequent and distressing symptom of schizophrenia, associated with physical, emotional, and cognitive challenges. Despite their clinical importance, changes in the multiple dimensions of AVHs during treatment have rarely been examined, and subjective views thereof have received minimal attention. Here, we evaluated 87 patients with schizophrenia-related AVHs using the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ; a self-report questionnaire) and the Psychotic Symptom Rating Scales-Auditory Hallucination Subscale (PSYRATS-AH; a clinician-rated scale) at baseline and after 6 months and 1 year of treatment. We explored dimensions that changed from the perspectives of both clinicians and patients and the relationships between these perceptions over the year. The test-retest reliabilities of the HPSVQ and PSYRATS-AH were generally fair. Improvements in AVHs were evident over the first 6 months; the PSYRATS-AH revealed a broader range of symptom improvement than did the HPSVQ. The "interference with life" dimension on the HPSVQ was not reduced, but the "disruption to life" score on the PSYRATS-AH was. At both baseline and 6 months, the physical characteristics of AVHs (frequency, duration, and loudness) were significantly correlated with both distress and life interference/disruption; all correlations except that for frequency were reduced at 1 year. The clinician-rated and self-reported personal perspectives on AVHs exhibited both differences and similarities; physical AVH components and subjective distressful experiences changed in different ways in those with chronic, persistent AVHs. The HPSVQ and PSYRATS-AH data were complementary, improving our understanding of the clinical implications of AVHs and subjective patient distress.

Long-term clinical efficacy of maintenance electroconvulsive therapy in patients with treatment-resistant schizophrenia on clozapine.

Electroconvulsive therapy (ECT) has been suggested as a treatment for augmenting the response to clozapine in patients that do not respond well to clozapine alone and maintenance ECT (M-ECT) had also been recommended to sustain improvement. This retrospective study of up to 2 years of observation was conducted to explore whether M-ECT is beneficial for long-term maintenance of the symptom remission elicited by acute ECT. Positive and Negative Syndrome Scale (PANSS) were plotted for each patient and compared using a linear mixed-effect model. A total of thirty-eight patients were followed and classified into three groups: (1) clozapine alone (CZP, n = 15), (2) acute ECT only (A-ECT, n = 11), and (3) acute ECT with M-ECT (M-ECT, n = 12). The mean number and interval of ECT sessions during the maintenance period in the M-ECT group were 39.0 ±â€¯26.7 and 15.6 ±â€¯8.4 days, respectively. The slope of the M-ECT group eventually declined, but that of the A-ECT group gradually increased back to the pre-ECT level. No persistent or serious adverse effects were observed. In conclusion, A-ECT augmented the effect of clozapine, but M-ECT was required for sustaining symptom improvement.

Long-Term Changes in Self-Report Auditory Verbal Hallucinations in Patients with Schizophrenia Using Clozapine.

This study explored long-term changes in self-report auditory verbal hallucinations (AVHs) among patients with schizophrenia taking clozapine. Forty-four patients who were evaluated more than twice and were above the mild severity category on the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) were enrolled. The mean observation period was 492.5±350.1 days (median, 452 days). The mean total, physical, and emotional factor scores on the HPSVQ were significantly reduced from baseline to the final observations except for one item "interference with life," which was not significantly reduced. Regarding the time-dependent longitudinal changes modeled using linear mixed-effect regression, the total and physical factor scores showed significant changes during the first year, but the emotional factor score did not satisfy a more stringent level of significance. Female gender was negatively associated with the reduction in total and physical factor scores. The duration of treatment with clozapine also had a negative relationship with the reductions in all three scores.

Association between electroencephalogram changes and plasma clozapine levels in clozapine-treated patients.

This retrospective observational study was performed to investigate electroencephalogram abnormalities in clozapine-treated patients with refractory schizophrenia or bipolar disorder. The electroencephalogram and plasma clozapine and norclozapine levels in 71 patients were measured on the same day. Fifty-nine patients (85.9%) had a diagnosis of schizophrenia, and 12 patients (14.1%) had a diagnosis of bipolar disorder. The mean daily clozapine dose was 242.9 ± 105.5 mg (range 25-500 mg), and the mean plasma clozapine and norclozapine levels were 429.4 ± 264.1 and 197.8 ± 132.6 ng/ml, respectively. Twenty-five patients (35.2%) were taking valproate in combination with clozapine. electroencephalogram abnormalities were found in 51 (71.8%) patients. No patient reported clinical seizures. Plasma clozapine level was significantly associated with electroencephalogram abnormalities and was identified as a significant predictor of electroencephalogram abnormalities in a logistic regression analysis. The plasma norclozapine levels of patients taking both clozapine and valproic acid were significantly lower than those of patients treated with clozapine alone. These results demonstrate that electroencephalogram abnormalities are closely correlated with plasma clozapine levels. Valproate reduced plasma norclozapine levels. Simultaneous monitoring of electroencephalogram and plasma clozapine levels was useful for adjusting clozapine doses, improving clinical efficacy, and preventing the side effects of clozapine treatment.

Combination of Electroconvulsive Therapy and Clozapine in Treatment-Resistant Schizophrenia.

OBJECTIVE: This study aimed to investigate the effectiveness and tolerability of the combination of electroconvulsive therapy (ECT) in patients with clozapine-treated schizophrenia. METHODS: Patients with clozapine-treated schizophrenia during five years of pre-determined period were recruited from Electronic Medical Record. Clinical effects of acute ECT on psychotic symptoms were investigated. We also tried to identify predictive variables requiring maintenance treatment of ECT. RESULTS: Fourteen patients received ECT and clozapine and sixteen were treated with clozapine alone. In the ECT group, which could be refined as clozapine-resistance, PANSS total score was significantly reduced by 19.0±9.9 points, corresponding to a reduction rate of 18.5±8.3%. The clinical remission defined as 20% PANSS reduction criteria was achieved at 42.9%. The subscale factors were significantly reduced, among which the negative symptom was the least. There was no difference in demographic and clinical information between patients receiving and not receiving maintenance ECT, and not all patients seemed to need maintenance ECT if clozapine is continued. CONCLUSION: Combination of ECT and clozapine in patients with clozapine-resistant schizophrenia resulted in a rapid and substantial reduction of psychotic symptoms. Further studies are needed to improve the effectiveness and tolerability of ECT.

Long-Term Evolution of Metabolic Status in Patients with Schizophrenia Stably Maintained on Second-Generation Antipsychotics.

OBJECTIVE: Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Despite the risk of MetS, SGAs may have to be continued with change in some patients. The aim of this study was to trace the evolution of MetS in these patients. METHODS: Patients with schizophrenia who had been maintained on a fixed SGA regimen for more than a year were followed-up without changing the regimen. Metabolic indicators were evaluated at baseline and at follow-up. Prevalence, incidence and spontaneous normalization rate of MetS were estimated. Risk factors that might have influenced the evolution were scrutinized. RESULTS: A total of 151 subjects were included. During the mean observation period of 389.9±162.4 days, the prevalence of MetS was increased from 35.1 to 45.0%. The incidence rate was 29.6%, while the normalization rate was 26.4%, risk factors affecting incidence were age (OR=1.09, 95% CI: 1.03-1.17), baseline continuous values of metabolic syndrome risk scores (cMetS, OR=1.77, 95% CI:1.29-2.55) and baseline body weight (OR=1.06, 95% CI: 1.01-1.13). Normalization was influenced by age (OR=0.74, 95% CI: 0.57-0.89) and baseline body weight (OR=0.85, 95% CI: 0.72-0.95). CONCLUSION: The prevalence of MetS steadily increased with the continuous use of SGAs. However, individual difference was extensive and about a quarter of the patients were able to recover naturally without specific measurements.

Comparison of clinician-rated and self-report insight in Korean patients with schizophrenia using VAGUS insight scale.

This study was aimed to explore self-report auditory verbal hallucinations to provide unique and valuable information in addition to clinician-rated assessment in patients with schizophrenia. The VAGUS (http://www.vagusonline.com) is a recently developed insight scale that includes both clinician-rated (CR) and self-report (SR) versions. Insight measures obtained by the two versions of the VAGUS from the clinicians and the patients, respectively, in forty-one patients diagnosed with schizophrenia by DSM-IV-TR criteria were compared. Correlation coefficients for inter-scale convergence and 3-D biplots for multivariate relationship were derived from the subscales of the VAGUS. For external validation, correlation analyses with abridged version of Scale to Assess Unawareness in Mental Disorder (SUMD-A) and PANSS G12 item were conducted. Total scores of VAGUS-CR and -SR were 5.2 ± 2.6 and 4.9 ± 2.2, respectively. There was a strong correlation between them along with moderate pairwise correlations among the subscales. The 3-D biplots demonstrated that most subscales were clustered as a single factor apart from self-report Symptom Attribution separated as an independent factor. The VAGUS-CR, not -SR correlated significantly with the SUMD-A and PANSS G12. The utility of the VAGUS in reaching more overall understanding of the elusive phenomenon of insight in patients with schizophrenia is discussed.

Effectiveness of Electroconvulsive Therapy Augmentation on Clozapine-Resistant Schizophrenia.

OBJECTIVE: This retrospective case series study of the effectiveness of electroconvulsive therapy (ECT) augmentation on clozapine-resistant schizophrenia was conducted by EMR review. METHODS: Clozapine-resistance was defined as persistent psychotic symptoms despite at least 12 weeks of clozapine administration with blood levels over 350 ng/mL in order to rule out pseudo-resistance. Seven in-patients who were taking clozapine and treated with ECT were selected. We analyzed the psychopathology and subscales changed by ECT. RESULTS: The average number of ECT sessions was 13.4 (±4.6). Total Positive and Negative Syndrome Scale (PANSS) score was significantly reduced by 17.9 (±12.8) points (p=0.0384) on average, which represented a reduction of 25.5% (±14.3). 71.4% (5/7) of patients were identified as clinical remission, with at least a 20% reduction in PANSS score. PANSS reduction was associated with number of ECT sessions, stimulus level in the final session, and blood clozapine levels before ECT. However, the negative subscale on the PANSS were not reduced by ECT in any patient. We did not observe any persistent adverse cognitive effects. CONCLUSION: This study supports that ECT augmentation on clozapine-resistant schizophrenia reveals clinically effective and safe. Further research should be done involving a larger number of patients to investigate the effectiveness of clozapine/ECT combination therapy.

Clozapine Improves Memory Impairment and Reduces Aß Level in the Tg-APPswe/PS1dE9 Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive degenerative condition. In order to treat AD, the use of a "drug repositioning" or "repurposing" approach with potential disease-modifying compounds has been increased. The new generation antipsychotics are commonly used in AD and other dementias for the treatment of psychosis and behavioral symptoms, and several animal models have shown the effects of these potential disease-modifying compounds. In this study, we examined whether long-term clozapine treatment could reduce amyloid beta (Aß) deposition and cognitive impairment in transgenic mice of AD, Tg-APPswe/PS1dE9. AD mice were fed clozapine at 20 mg/kg/day for 3 months from 4.5 months of age. Intake of clozapine improved the Aß-induced memory impairment and suppressed Aß levels and plaque deposition in the brain of AD mice. Clozapine upregulated Trk, brain-derived neurotrophic factor, cyclin-dependent kinase-5, and p35 in the cortex and hippocampus of AD mice and activated AMP-activated protein kinase (AMPK). As a downstream effector of AMPK, beta-secretase expression was decreased by clozapine administration. Moreover, clozapine-phosphorylated synapsin I at Ser9 and Ser549 sites in the hippocampus and cortex of AD mice, which may be involved in synaptic strength. This study suggests that as one of candidate for multi-target approach of AD treatment, clozapine is proposed as a therapeutic drug for treatment of AD patients.

Prevalence and Correlates of DSM-IV Mental Disorders in South Korean Adults: The Korean Epidemiologic Catchment Area Study 2011.

OBJECTIVE: The aim of this study was to estimate the prevalence and correlates of mental disorders in Korean adults. METHODS: Door to door household surveys were conducted with community residents aged 18-74 years from July 19, 2011, to November 16, 2011 (n=6,022, response rate 78.7%). The sample was drawn from 12 catchment areas using a multistage cluster method. Each subject was assessed using the Korean version of the World Health Organization Composite International Diagnostic Interview (CIDI) based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). RESULTS: Lifetime and 12-month prevalence estimates were as follows: alcohol use disorders, 13.4% and 4.4%, respectively; nicotine use disorders, 7.2% and 4.0%, respectively; anxiety disorders, 8.7% and 6.8%, respectively; and mood disorders, 7.5% and 3.6%, respectively. The prevalence rates of all types of DSM-IV mental disorders were 27.6% and 16.0%, respectively. Being female; young; divorced, separated, or widowed; and in a low-income group were associated with mood and anxiety disorders after adjustment for various demographic variables, whereas being male and young were associated with alcohol use disorders. Higher income was not correlated with alcohol use disorder as it had been in the 2001 survey. CONCLUSION: The rate of depressive disorders has increased since 2001 (the first national survey), whereas that of anxiety disorders has been relatively stable. The prevalence of nicotine and alcohol use disorders has decreased, and the male-to-female ratio of those with this diagnosis has also decreased.

Differences in the internal structure of hallucinatory experiences between clinical and nonclinical populations.

We investigated differential patterns of hallucinatory experiences between nonclinical and clinical samples. A total of 223 nonclinical individuals (108 females) and 111 subjects with schizophrenia (54 females) completed the Launay-Slade Hallucination Scale-Revised (LSHS-R) and Perceptual Aberration Scale (PAS). The Minnesota Multiphasic Personality Inventory-2 (MMPI-2) was used for the nonclinical group, and the Positive and Negative Syndrome Scale (PANSS) hallucination item was used for the clinical group. Cronbach's alpha values showed good internal consistency for the LSHS-R. In the two groups, significant associations were found between LSHS-R and PAS scores. Two factors were extracted through a principal component analysis (PCA) in the nonclinical group, and three factors were identified in the clinical group. The results of a hierarchical cluster analysis (HCA) revealed that a perception-cognition dimension was clear cluster discriminating element for the nonclinical group, whereas alterations in perception-cognition dimension were characteristic in cluster structure of the clinical group. Our findings suggest that the nature of hallucinatory experiences may differ qualitatively between a nonclinical population and subjects with schizophrenia. Perceptual or cognitive aberrations may add a psychopathologic dimension to hallucinatory experiences. Exploring the internal structure of hallucinatory experiences may provide explanatory insight into these experiences in the general population.

Clozapine induces chloride channel-4 expression through PKA activation and modulates CDK5 expression in SH-SY5Y and U87 cells.

OBJECTIVES: Second-generation antipsychotic drugs, such as clozapine, were reported to enhance neurite outgrowth by nerve growth factor in PC12 cells. The authors previously showed that chloride channel 4 (CLC-4) is responsible for nerve growth factor-induced neurite outgrowth in neuronal cells. In this study, we examined whether clozapine induces CLC-4 in neuroblastoma and glioma cells. METHODS: The effect of clozapine on CLC-4 expression was examined in neuroblastoma (SH-SY5Y) and glioma (U87) cells. To investigate the signaling pathway responsible for clozapine-induced CLC-4 expression, the phosphorylation of cAMP response element-binding protein (CREB), which binds CRE in the promoter of the human CLC-4 gene, was examined. To identify the target of clozapine induced CLC-4, CLC-4 siRNA was introduced to neuroblastoma and glioma cells for functional knockdown. RESULTS: We observed that clozapine increased CLC-4 expression in both SH-SY5Y and U87 cells. Clozapine induced CREB phosphorylation, but in the presence of inhibitor of protein kinase A (an upstream kinase of CREB) clozapine-induced CLC-4 expression was suppressed. Finally, we found that CLC-4 knockdown suppressed clozapine-induced cyclin-dependent kinase 5 (CDK5) expression in SH-SY5Y and U-87 cells suggesting CDK5 as potential molecular target of clozapine induced CLC-4 expression. CONCLUSIONS: The results of the present study suggest that clozapine's therapeutic effect may include the induction of CLC-4 which is dependent on CREB activation via PKA. We also found that functional knockdown of CLC-4 resulted in reduction of CDK5 expression, which may also be implicated in clozapine's therapeutic effect.

Lifetime risk and age of onset distributions of psychiatric disorders: analysis of national sample survey in South Korea.

BACKGROUND: The present study represents the first attempt at examining variation across Korean cohorts with respect to lifetime risk of DSM-IV psychiatric disorders. AIMS: To present data on lifetime prevalence and projected lifetime risk, as well as age of onset (AOO) and demographic correlates of DSM-IV psychiatric disorders as assessed in the nationwide survey of a representative sample of Korean adults. METHOD: The survey was based on a multistage area probability sample of non-institutionalized Koreans aged 18-64 years. The Korean version of the Composite International Diagnostic Interview 2.1 (K-CIDI 2.1) was administered by lay interviewers. RESULTS: Lifetime prevalence of any disorder was 24.6%. Alcohol abuse (9.2%), alcohol dependence (7.0%), major depressive disorder (5.6%), specific phobia (3.8%), and GAD (1.6%) were the most common disorders. The median AOO was earliest for anxiety disorders (age 29), latest for mood disorders (age 47), and intermediate for alcohol use disorders (age 31). Compared to observed lifetime prevalence (24.6%), 35.0% of Koreans will eventually experience one of these disorders. Further, half of the population who present with a psychiatric disorder do so by the age of 32 and younger cohorts are at greater risk for most disorders. CONCLUSIONS: About one-third of the Korean adult population will meet the criteria for a DSM-IV psychiatric disorder at some time during their life. The median age of onset varies from disorder to disorder and younger cohorts appear to be at greater risk for most disorders.