Associations between the neuron-specific glucocorticoid receptor (NR3C1) Bcl-1 polymorphisms and suicide in cancer patients within the first year of diagnosis.

BACKGROUND: Cancer diagnosis is associated with an increased suicide risk, particularly within the first 1 year after diagnosis of cancer. Abnormal function of the hypothalamic-pituitary-adrenal axis has been implicated in the pathophysiology of depression and suicide. We examined genetic associations of the functional Bcl-1 polymorphism of (rs41423247) neuron-specific glucocorticoid receptor (NR3C1) gene, with death by suicide in cancer patients. Suicides occurring within a year of cancer diagnosis ('early suicide') were considered separately from those suicides during the second or subsequent year ('late suicide') after cancer diagnosis. METHODS: The subjects consisted of 343 cancer patients admitted to a general hospital in Seoul, South Korea from 1996 to 2009, of which 182 had died by suicide and 161 were alive on December 31, 2009. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue sample of patients with cancer. We conducted a case-control association analysis of Bcl-1 polymorphism of NR3C1 gene. RESULTS: Subjects carrying the GG genotype of Bcl-1 polymorphism were at increased risk of early suicide when compared to those carrying the CC genotype (OR 3.80, 95 % CI 1.02-14.16, p = .047). Similarly, those individuals carrying the GG genotype (recessive mode) had an increased risk of early suicide relative to the CC or CG genotype (OR 3.71, 95 % CI 1.03-13.43, p = .045). However, there were no differences in the genotype distributions of the NR3C1 Bcl-1 polymorphism between late suicide cases and controls. CONCLUSIONS: Our findings suggest that the NR3C1 Bcl-1 polymorphisms may be involved in the susceptibility to suicide within the first year after cancer diagnosis among cancer patients in Korean population.

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.

Lifetime psychopathological characteristics associated with comorbid obsessive-compulsive disorder in clinically stable patients with chronic schizophrenia.

Obsessive-compulsive symptoms (OCS) commonly occur in the course of schizophrenia. The aim of this study was to investigate the rate of obsessive-compulsive disorder (OCD) in patients with chronic schizophrenia and evaluate lifetime correlates of the comorbidity. Subjects were clinically stable patients with chronic schizophrenia (n = 320). Patients having comorbid OCD and those without OCD were compared in terms of symptoms dimensions and cognitive function. OCD was found in 20.6 % of subjects. Earlier age at onset, male gender, higher level of education, comorbid panic disorder, and specific phobia were associated with comorbid OCD. In terms of lifetime symptoms, depression (p = 0.001) and anxiety (p = 0.014) showed significant association with the comorbidity, which corroborates with our previous study findings regarding OCD in bipolar disorder. In addition, decreased emotional response (p = 0.016), less formal thought disorder (p = 0.007), and less prodromal impairment (p = 0.005) were independently associated with the comorbidity. The OCD group showed better performance in working memory domain (p = 0.027) while other cognitive domains did not show any significant difference between the two groups. Association of OCSs with depressive symptoms and other comorbid anxiety disorders seems to be a common finding across schizophrenia and bipolar disorder. This study also suggests that comorbidity of OCD in schizophrenia is associated with less impairment of thought process and cognitive function throughout the disease course.

Psychosocial Issues Related to Donor's Decision-Making in Living Donor Liver Transplantation.

BACKGROUND The aim of this study was to investigate the detailed motives, concerns, and psychological defensiveness of living liver donor candidates in a Korean population. MATERIAL AND METHODS We analyzed data of 102 donor candidates obtained from routine psychosocial evaluation for living donor liver transplantation (LDLT) using descriptive methods. Donor candidates completed 2 questionnaires regarding their motivations and concerns, as well as a validity scale, the K scale from the Minnesota Multiphasic Personality Inventory-2. RESULTS Donor candidates were more likely to cite family-related issues (77.5% to 94.1%) including well-being of the whole family and family affection as the reasons for their liver donation rather than personal motives (38.2% to 57.8%). Donors were also more likely to concern about the recipient's survival and recovery (52.9% to 58.8%) rather than their own difficulties such as surgical complications and occupational disadvantages (19.6% to 38.2%). Twenty-six donors (25.5%) took a psychologically defensive attitude (T-score of K scale ≥65) during the pre-donation evaluation. Psychologically defensive donors expressed a significantly lower level of concern about liver donation compared to non-defensive donors (P<0.01). CONCLUSIONS We need to pay more attention to the family-related issues and psychological defensiveness of living liver donor candidates when evaluating psychosocial status before LDLT.

The effect of MK-801 on mTOR/p70S6K and translation-related proteins in rat frontal cortex.

In experimental animals, including rats, MK-801 produces characteristic behavioural changes that model schizophrenia. It has been hypothesized that these changes accompany long-term synaptic changes, which require protein neosynthesis. We observed the effect of MK-801 on the "mammalian target of rapamycin" (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) pathway that regulates protein synthesis in the rat frontal cortex. A single injection of MK-801 (0.5, 1, or 2mg/kg) induced an acute increase in the phosphorylation of Akt (Ser-473) eIF4E-binding protein (4E-BP1) (Thr-37/46) and p70S6K (Thr-389). In contrast, after repeated treatment with MK-801 (1mg/kg for 5 or 10 days), the phosphorylation of Akt (Ser-473), mTOR (Ser-2481), 4E-BP1 (Thr-37/46), p70S6K (Thr-389), and S6 (Ser-240/244) increased. Thus, proteins in the mTOR/p70S6K pathway are modulated in chronic MK-801 animal models. These findings may suggest that repeated MK-801 treatment activates the signal transduction pathways involved in the initiation of protein synthesis in the rat frontal cortex.

Linkage and Association Analyses of Schizophrenia with Genetic Variations on Chromosome 22q11 in Koreans.

OBJECTIVE: Chromosome 22q11 has been implicated as a susceptibility locus of schizophrenia. It also contains various candidate genes for which evidence of association with schizophrenia has been reported. To determine whether genetic variations in chromosome 22q11 are associated with schizophrenia in Koreans, we performed a linkage analysis and case-control association study. METHODS: Three microsatellite markers within a region of 4.35 Mb on 22q11 were genotyped for 47 multiplex schizophrenia families, and a non-parametric linkage analysis was applied. The association analysis was done with 227 unrelated patients and 292 normal controls. For 39 single nucleotide polymorphisms (SNPs) spanning a 1.4 Mb region (33 kb interval) containing four candidate schizophrenia genes (DGCR, COMT, PRODH and ZDHHC8), allele frequencies were estimated in pooled DNA samples. RESULTS: No significant linkage was found at any of the three microsatellite markers in single and multi-point analyses. Five SNPs showed suggestive evidence of association (p<0.05) and two more SNPs showed a trend for association (p<0.1) in pooled DNA association analysis. Individual genotyping was performed for those seven SNPs and four more intragenic SNPs. In this second analysis, all of the 11 SNPs individually genotyped did not show significant association. CONCLUSION: The present study suggests that genetic variations on chromosome 22q11 may not play a major role in Korean schizophrenia patients. Inadequate sample size, densities of genetic markers and differences between location of genetic markers of linkage and association can contribute to an explanation of the negative results of this study.

Activation of Cdk2-pRB-E2F1 cell cycle pathway by repeated electroconvulsive shock in the rat frontal cortex.

BACKGROUND: Recent reports indicate that repeated electroconvulsive shock (ECS) induces cortical cell proliferation, suggesting the possibility that ECS may activate cell cycle progression in the rat brain cortex. METHODS: Sprague-Dawley rats (150-200g) were divided into four treatment groups and then given sham treatment or ECS treatment for 1, 5, and 10 days, respectively. The activity of cyclin-dependent kinase 2 (Cdk2), phosphorylation, and total protein amount of cyclin D1, cyclin E, pocket retinoblastoma family of protein (pRB), and E2F1 were analyzed in the rat cerebral cortex. RESULTS: The activity of Cdk2, the protein amount of pRB, Ser795 phosphorylation of pRB, and the protein amount of E2F1 were all increased compared with the sham-treated control subjects, and these increases were enhanced with the increasing number of ECS. In contrast, the protein amounts of Cdk2, cyclin D1, and cyclin E were not changed by repeated ECS. CONCLUSIONS: The Cdk2-pRB-E2F1 cell cycle pathway is activated by repeated ECS in the rat frontal cortex.

Region-specific phosphorylation of ERK5-MEF2C in the rat frontal cortex and hippocampus after electroconvulsive shock.

ERK5-MEF2C has been implicated in many aspects of neuronal survival and neuroprotection. Neurotrophic effects have been considered as one of the mechanisms in therapeutic electroconvulsive shock (ECS). To investigate whether ECS activates ERK5-MEF2C, we examined the phosphorylation of ERK5, along with its downstream molecule MEF2C, after ECS in the rat frontal cortex and hippocampus. Increased phosphorylation of ERK5 was observed immediately after ECS, but was barely detectable from 2 min after ECS in both the frontal cortex and the hippocampus. The level of MEF2C phosphorylation was decreased immediately after ECS in both regions. It was increased from 2 min and maintained until 10 min after ECS in the frontal cortex, but it returned to the basal level from 2 min after ECS in the hippocampus. Taken together, these results suggest that ECS can regulate the region-specific activity of ERK5-MEF2C pathways in the rat brain.

The effects of clozapine on the GSK-3-mediated signaling pathway.

We investigated the effect of 10 microM clozapine on the activity of glycogen synthase kinase-3beta (GSK-3beta) and its upstream and downstream molecules in SH-SY5Y human neuroblastoma cells. Clozapine activates both Akt- and Dvl-mediated phosphorylation of GSK-3beta through phosphorylation at Ser9, and increased total cellular and intranuclear levels of beta-catenin. Pretreatment with the specific inhibitor of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, LY294002 (20 microM), prevented the phosphorylation of Akt but did not affect the phosphorylation of GSK-3beta. These results suggest that clozapine regulates the phosphorylation of GSK-3beta through Wnt signal pathways involving Dvl upstream but not through the PI3K-Akt pathway in SH-SY5Y cells.

Phosphorylation of glycogen synthase kinase-3beta at serine-9 by phospholipase Cgamma1 through protein kinase C in rat 3Y1 fibroblasts.

Phospholipase Cgamma1 (PLCgamma1) plays an important role in controlling cellular proliferation and differentiation. PLCgamma1 is overexpressed in some tumors, and its overexpression induces solid tumors in nude mice. However, the regulatory mechanisms underlying PLCgamma1-induced cell proliferation are not fully understood. Here we show that overexpression of PLCgamma1 highly phosphorylated glycogen synthase kinase-3beta (GSK-3beta) at serine-9 in 3Y1 fibroblasts. Inhibition of protein kinase C (PKC)s with GF109203X abrogated GSK-3beta phosphorylation by PLCgamma1. We also found that steady-state level of cyclin D1 protein, but not cyclin D1 mRNA, was highly elevated in response to serum stimulation in PLCgamma1-transfected cells as compared with vector-transfected cells. Since GSK-3beta is involved in cyclin D1 proteolysis in response to mitogenic stimulation, PLCgamma1-mediated GSK-3beta phosphorylation may function as a regulation of cyclin D1 accumulation in PLCgamma1-overexpressing cells.

Differential regulation of FAK and PYK2 tyrosine phosphorylation after electroconvulsive shock in the rat brain.

It has been suggested that FAK and PYK2 have differential regulatory pathways and differential functions in the central nervous system. The authors have previously reported that electroconvulsive shock (ECS) activates PYK2 mediated signaling in the rat hippocampus. In the present article, the authors examined the effect of ECS on PYK2 and FAK mediated signaling in the rat cerebral cortex and hippocampus. Our results showed that ECS activated PYK2 more preferentially than FAK in both the cortex and the hippocampus. The association of Src-family kinases with FAK and PYK2 was also distinctively affected by ECS; Src was mainly associated with PYK2 while Yes was associated with FAK. The phosphorylation of FAK and PYK2 at the key tyrosine residue was not well correlated with the association with Src-family kinases.

Heart rate dynamics and their relationship to psychotic symptom severity in clozapine-treated schizophrenic subjects.

The analysis of heart rate variability (HRV) has proven to be useful in evaluating the neuroautonomic dysfunctions associated with various clinical conditions. The purpose of this study was to investigate the linear and non-linear dynamic measures of HRV, and to evaluate their relationship with the psychotic symptom severity, in clozapine-treated schizophrenic subjects. Fifty schizophrenic patients treated with clozapine as monotherapy and 50 normal control subjects were evaluated for HRV analysis. The HRV measurements were obtained from a 30-min resting electrocardiogram (ECG). The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). In the patient group, the complexity and symbolic dynamics measures as well as the time and frequency domain measures of HRV were significantly lower than in the control group (P<0.01). The intermediate-term fractal scaling component value was significantly higher in the patient group (P<0.01). The PANSS total score and the positive symptom subscale score had significant negative correlations with the sample entropy (SampEn) value (P<0.01). In conclusion, schizophrenic patients treated with clozapine had markedly different heart rate dynamics compared to normal control subjects. The severity of psychotic symptoms was associated with the SampEn value, suggesting that the non-linear complexity measure might be useful in assessing the neuroautonomic dysfunction in schizophrenia.

Uncontrolled self-medication with venlafaxine in a patient with major depressive disorder.

Antidepressants are known to have no significant ability to cause addiction. However, a recent study showed many individuals with mood disorders self-medicated with antidepressants to relieve symptoms. We report here a male physician, diagnosed five years ago with major depressive disorder, with insomnia, anxiousness, and chest heaviness. He began self-medicating with 150 mg of venlafaxine daily, without any monitoring. During his most recent severe depressive episode, he was taking up to 1,500 mg of venlafaxine daily. Without this medication, he experienced discontinuation syndrome, which included severe anxiety, chest heaviness, and breathing difficulty, and which he judged as indicating a more severely depressed state. He also experienced overdose symptoms, such as hypertension and tachycardia. He attempted suicide with drugs that he possessed. In conclusion, careful monitoring is needed when treating patients with venlafaxine, because its discontinuation syndrome is similar to symptoms of major depressive disorder, and suicidality may result from an overdose.

Altered cell viability and proliferation activity of peripheral lymphocytes in patients with Alzheimer's disease.

OBJECTIVE: We evaluated cell viability and proliferation activity of peripheral lymphocytes as potential models of neuronal death in Alzheimer's disease (AD). METHODS: We analyzed the cell viability and proliferation activity of phytohemagglutinin (PHA)-activated lymphocytes from 68 AD patients and 33 normal controls. The cellular measures were made at baseline (0 hr), 24 hrs, 48 hrs, 72 hrs, and 96 hrs after PHA stimulation. RESULTS: Cell viability in the AD patients was significantly decreased at 72 hrs and 96 hrs, compared with the normal controls. The declining ramp of the proliferation activity from 48 hrs to 72 hrs after PHA stimulation was significantly related to cell viability at 72 hrs and at 96 hrs in the AD patients. CONCLUSION: Lymphocytes from patients with AD have altered viability and proliferation characteristics in culture following PHA stimulation. These findings suggest that lymphocytes may be used as a peripheral tissue model of cell cycle dysregulation in AD.

Early trauma and lifetime suicidal behavior in a nationwide sample of Korean medical students.

BACKGROUND: No previous study has investigated the association between early trauma and suicidal behavior in medical students. We evaluated the types of early trauma which are the most strongly associated with a lifetime history of suicidal behavior in medical students. METHOD: A total of 6986 medical students completed a self-administered questionnaire (response rates: 49.6% of the entire medical student body in Korea) which included lifetime suicidal behavior, stressors, and the Early Trauma Inventory Self Report-Short Form (ETISR-SF). This was used to evaluate the most serious forms of trauma experienced before the age of 18, including general trauma, physical, emotional and sexual abuse. RESULTS: Among medical students, lifetime prevalence of suicidal behavior was 34.0% for those who experienced early trauma and 18.1% in those without a history of trauma (chi(2)=215.7, p<0.0001). Emotional abuse exhibited a higher odds ratio for lifetime suicidal behavior (OR=3.6, 95%CI=2.9-4.4) than other traumas including general trauma (OR=2.1, 95%CI=1.8-2.4), sexual (OR=2.0, 95%CI=1.5-2.8) or physical (OR=1.8, 95%CI=1.5-2.1) abuse, and current stressors including heavy stress (OR=1.5, 95%CI=1.4-1.8), poor physical health (OR=1.3, 95%CI=1.2-1.5), and poor economic status (OR=1.2, 95%CI=1.0-1.3). Emotional abuse also showed a higher odds ratio for lifetime suicidal ideation (OR=3.5, 95%CI=2.8-4.4), plan (OR=3.9, 95%CI=2.4-6.2), and attempt (OR=4.1, 95%CI=2.4-6.8) than other early traumas or stressors. In emotional abuse, a continuously cold or uncaring parental attitude exhibited a stronger association with lifetime suicidal behavior (OR=4.5, 95%CI=2.7-7.7) than other emotional abuse. CONCLUSION: Emotional abuse, especially continuous parental emotional abuse in childhood, is significantly associated with lifetime suicidal behavior in Korean medical students.

Association between Painful Physical Symptoms and Clinical Outcomes in Korean Patients with Major Depressive Disorder: A Three-Month Observational Study.

OBJECTIVE: This paper aims to examine the association between painful physical symptoms (PPS) and major depressive disorder (MDD) in a naturalistic clinical practice setting within a Korean population. METHODS: Patients with acute MDD that joined a multicountry, observational, three-month study in six Asian countries and regions were classified as PPS+ (mean score >/=2) and PPS- (mean score <2) using the modified Somatic Symptom Inventory. In this analysis, we report the results from the Korean subset, where depression severity was assessed using the Clinical Global Impression of Severity (CGI-S) scale and 17-item Hamilton Depression Rating Scale (HAMD(17)). Pain severity was measured using a visual analogue scale (VAS), while the EuroQoL (EQ-5D) assessed patient well-being. RESULTS: Of 198 patients, 45.96% (91/198) of patients were classified as PPS+, of which 78.02% (71/91) were women. PPS+ patients had significantly more severe depression at baseline {CGI-S score, mean [standard deviation (SD)], PPS+: 5.09 [0.79]; PPS-: 4.63 [0.76]; p<0.001; HAMD(17) total score, mean [SD], PPS+: 24.34 [5.24]; PPS-: 20.76 [5.12]; p<0.001} and poorer quality of life [EQ-5D overall health state, mean (SD), PPS+: 39.37 (20.52); PPS-: 51.27 [20.78]; p<0.001] than PPS- patients. Both groups improved significantly (p<0.001) in depression and pain severity outcomes, as well as quality of life by endpoint, but no significant within-group baseline-to-endpoint change wase observed. CONCLUSION: The frequency of PPS was common in Korean patients with MDD, and was associated with more severe depression, poorer quality of life, and a trend towards poorer clinical outcome.

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.

The effects of repeated administrations of MK-801 on ERK and GSK-3beta signalling pathways in the rat frontal cortex.

Repeated administrations of NMDA receptor antagonists induce behavioural changes which resemble the symptoms of schizophrenia in animals. ERK and GSK-3beta associated signalling pathways have been implicated in the pathogenesis of psychosis and in the action mechanisms of various psychotropic agents. Here, we observed the phosphorylations of ERK and GSK-3beta and related molecules in the rat frontal cortex after repeated intraperitoneal injections of MK-801, over periods of 1, 5, and 10 d. Repeated treatment with 0.5, 1, and 2 mg/kg MK-801 increased the phosphorylation levels of the MEK-ERK-p90RSK and Akt-GSK-3beta pathways and concomitantly and significantly increased CREB phosphorylation in the rat frontal cortex. However, single MK-801 treatment did not induce these significant changes. In addition, the immunoreactivities of HSP72, Bax, and PARP were not altered, which suggests that neuronal damage may not occur in the rat frontal cortex in response to chronic MK-801 treatment. These findings suggest that chronic exposure to MK-801 may induce pro-survival and anti-apoptotic activity without significant neuronal damage in the rat frontal cortex. Moreover, this adaptive change might be associated with the psychotomimetic action of MK-801.

Increased phosphorylation of Ser473-Akt, Ser9-GSK-3beta and Ser133-CREB in the rat frontal cortex after MK-801 intraperitoneal injection.

GSK-3beta is regarded as playing an important part in the pathogenesis of schizophrenia and the action of psychotomimetic agents. We observed phosphorylation of molecules associated with the GSK-3beta signalling pathway in the rat brain after MK-801 injection, which induces a schizophrenia-like state in humans. Ser9-GSK-3beta phosphorylation was increased after injection of 1 mg/kg MK-801 in the rat frontal cortex but not in the hippocampus or cerebellum. This increase peaked at 30 min and was maintained until 90 min after injection. The phosphorylation showed a dose-dependent increase up to 1 mg/kg MK-801, followed by a decrease at higher dosage. Furthermore, phosphorylation of Ser473-Akt and Ser133-CREB showed similar temporal, dose-dependent and regionally specific patterns with those of Ser9-GSK-3beta. However, phosphorylation of Dvl and Ser33-beta-catenin was not affected by MK-801. These results suggest that GSK-3beta phosphorylation by MK-801 may be associated with the Akt-GSK-3beta pathway rather than with the Wnt-Dvl-GSK3beta pathway.