No Association of Functional Polymorphisms in Methlylenetetrahydrofolate Reductase and the Risk and Minor Physical Anomalies of Schizophrenia in Korean Population

Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism, plays an important role in DNA methylation. It has been suggested that abnormal DNA methylation contributes to the pathogenesis of schizophrenia and congenital anomalies. The previous findings regarding the genetic relationship between MTHFR and schizophrenia are controversial. This study investigated the association of the two functional polymorphisms of MTHFR, C677T and A1298C, with the risk for schizophrenia. Furthermore, we conducted an updated meta-analysis on the two polymorphisms. In addition, we investigated the relationship between the polymorphisms and minor physical anomaly (MPA), which may represent neurodevelopmental aberrations in 201 schizophrenia patients and 350 normal control subjects. There was no significant association between either of the two polymorphisms and the risk of schizophrenia (chi-square = 0.001, df = 1, P = 0.971 for C677T; chi-square = 1.319, df = 1, P = 0.251 for A1298C). However, in meta-analysis, the C677T polymorphism showed a significant association in the combined and Asian populations (OR = 1.13, P = 0.005; OR = 1.21, P = 0.011, respectively) but not in the Korean and Caucasian populations alone. Neither polymorphism was associated with MPAs measured by the Waldrop scale (chi-square = 2.513, df = 2, P = 0.285). In conclusion, the present findings suggest that in the Korean population, the MTHFR polymorphisms are unlikely to be associated with the risk for schizophrenia and neurodevelopmental abnormalities related to schizophrenia.

AKT1 Gene Polymorphisms and Obstetric Complications in the Patients with Schizophrenia

OBJECTIVE: We performed a genetic association study with schizophrenic patients to investigate whether the V-akt murine thymoma viral oncogene homolog 1 (AKT1) gene plays a role in obstetric complications. METHODS: One-hundred-eighty patients with schizophrenia (male, 113; female, 67) were included. All patients fulfilled DSM-IV criteria for schizophrenia. Obstetric complications were measured by the Lewis scale. Prenatal and perinatal information was retrospectively collected from the patients' mothers. We selected six single nucleotide polymorphisms (SNPs) for the AKT1 gene: SNP1 (rs3803300), SNP2 (rs1130214), SNP3 (rs3730358), SNP4 (rs 1130233), SNP5 (rs2494732), and SNPA (rs2498804). The genotype data were analyzed for an association with the Lewis total score in terms of allele, genotype, and haplotype distribution. RESULTS: The mean total Lewis scores were 1.30+/-1.61 for males and 1.54+/-1.87 for females. Higher total score tended to be correlated with an earlier age of onset of schizophrenia in females. In the total sample, no SNP was associated with obstetric complications. However, the additional analyses for male and female subgroups found a significant association between SNPA and SNP4 and Lewis score in females (p=0.02 for SNPA, p=0.04 for SNP4). The SNP5-SNPA haplotype showed a positive association with obstetric complications (p=0.03) in the female patient group. CONCLUSION: We found an association between SNPs in the AKT1 gene and total Lewis score measuring obstetric complications in female patients with schizophrenia. Because these findings did not survive a correction for multiple testing, the significance should be interpreted carefully and replication studies are required.

Voxel-Based Morphometry Study of Gray Matter Abnormalities in Obsessive-Compulsive Disorder

To examine regional abnormalities in the brains of patients with obsessive-compulsive disorder (OCD), we assessed the gray matter (GM) density using voxel-based morphometry (VBM). We compared magnetic resonance images (MRIs) acquired from 71 OCD patients and 71 age- and gender-matched normal controls and examined the relationship between GM density and various clinical variables in OCD patients. We also investigated whether GM density differs among the subtypes of OCD compared to healthy controls. We detected significant reduction of GM in the inferior frontal gyrus, the medial frontal gyrus, the insula, the cingulate gyrus, and the superior temporal gyrus of OCD patients. A significant increase in GM density was observed in the postcentral gyrus, the thalamus, and the putamen. Some of these regions, including the insular and postcentral gyrus, were also associated with the severity of obsessive- compulsive symptoms. These findings indicate that the frontal-subcortical circuitry is dysfunctional in OCD, and suggest that the parietal cortex may play a role in the pathophysiology of this disease.

Haloperidol and clozapine differentially regulate signals pstream of glycogen synthase kinase 3 in the rat frontal cortex

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Suicide-Related Behaviors among the College Students / 신경정신의학

OBJECTIVES: This study evaluated the prevalence of suicide-related behaviors (suicidal ideation, plan and attempt) and the status of depression, anxiety and function in college students. METHODS: A cross-sectional study was completed to a sample of 880 students with the self-administered form of Korean version of the Mini International Neuropsychiatric Interview (K-MINI), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). RESULTS: Estimated lifetime prevalence of suicidal ideation was 39.2%, that of suicidal plan was 4.7% and that of suicidal attempt was 3.0%. Students with any suicide-related behaviors showed higher lifetime prevalence of major and minor depression, higher BDI and BAI scores, and poor interpersonal relationship, adaptation to college life and physical health compared to the students with no suicide-related behaviors. The average points of grades during their college life were not significantly different according to kinds of suicide-related behaviors they experienced (F=0.39, p=0.82). 96% of suicidal attempters did not use mental health services. CONCLUSION: Results suggest that a high proportion of college students experience suicide-related behaviors. The students who had experienced suicide-related behaviors showed higher depression and anxiety and poorer function compared to students with no suicide-related behaviors. Most of suicidal attempters, however, did not use mental health service. Establishing campus mental health system is necessary to early detect mental health problems and to prevent suicide of college students.

Depressive Disorders among the College Students: Prevalence, Risk Factors, Suicidal Behaviors and Dysfunctions / 신경정신의학

OBJECTIVES: The purpose of this study was to investigate the prevalence and correlates of major and minor depressive disorders in college students. METHODS: A cross-sectional study was completed on a sample of 906 students (507 men and 399 women) with the self-administered form of Korean version of Mini International Neuropsychiatric Interview (K-MINI). RESULTS: Estimated 12-month prevalence of major depressive disorder was 4.2% in men and 9.5% in women, and that of minor depressive disorder was 15.4% in men and 23.2% in women. The factors, 'female gender' and 'age of 20-21', were significantly associated with major depressive disorder. 'Poor adaptation to school' was significantly associated with major depressive disorder both in men and women, but 'poor interpersonal relationship' and 'history of school withdrawal' were associated only in men. Idea of self-injury and suicidal behaviors (suicidal ideation, plan and attempt) were significantly associated with major depressive disorder in women, but were not associated with minor depressive disorder. CONCLUSION: Major and minor depressive disorders are highly prevalent in the college students. Major depressive disorder was more associated with dysfunctions and suicidal behaviors than minor depressive disorder. Campus-based mental health service is needed for the high-risk students.

The Effects of Repeated Electroconvulsive Shock on the Expression of NMDA Receptor Subunits in the Rat Hippocampus / 신경정신의학

OBJECTIVES: The N-methyl-D-aspartate (NMDA) receptor plays an important role in synaptic plasticity. The functional NMDA receptor is an oligomer of several subunits and the most abundant subunits in the brain are NR1, NR2A and NR2B. The function of the NMDA receptor is regulated by protein phosphorylation and by changes in the level of protein expression. The present study examined the effect of repeated electroconvulsive shock (ECS), an effective antidepressant and antipsychotic measure, on the expression of NMDA receptor subunit proteins in the rat hippocampus. METHODS: Male Sprague-Dawley rats were given 1, 5, or 10 consecutive daily ECS and the amounts of NR1, NR2A, and NR2B in the hippocampus were assessed by the immunoblot analysis. RESULTS: The expression levels of NR1 and NR2A subunits were found positively correlated with the number of treatment. However, there was no evidence of NR2B regulation by ECS. CONCLUSION: These findings suggest the action of ECS in the regulation of the NMDA receptor, and hence in the regulation of synaptic plasticity.

A Validation Study of Korean-version of Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS): Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) / 신경정신의학

OBJECTIVES: This study was conducted to develop the Korean version of Liverpool University Neuroleptic Side Effect Rating Scale(LUNSERS) for measuring neuroleptic side effects by self-rating method and to examine the reliability and validity in the schizophrenic patients medicated by neuroleptics and normal controls. METHODS: We made 51-item, 4-point scale of Korean version LUNSERS through translation, reverse translation and supervision by specialists. Sixty two schizophrenics diagnosed by DSM-IV criteria and medicated with neuroleptics completed LUNSERS twice with one week interval. Second LUNSERS and UKU side effect rating scale (UKU) by psychiatrist were administered to the schizophrenics at the same time. Normal controls also completed LUNSERS. RESULTS: The test-retest reliability (r=0.86, p<0.01) of LUNSERS and the concurrent validity (r=0.81, p<0.001) against UKU were good. But the neuroleptic doses and total scores of side effect items didn't show significant correlation. By the ROC curve analysis, the total scores of side effect items differentiated the medicated patients from non-medicated controls but not for the red herring items. CONCLUSION: Korean-version of LUNSERS has good reliability and validity. And it was also proved to be an useful assessment tool for measuring the extent of neuroleptic side effects systematically instead of UKU in clinical trials.

Atypical Antipsychotic Drug Induced Diabetes Mellitus / 신경정신의학

BACKGROUND: Atypical antipsychotics have been reported to affect glucose-insulin homeostasis and possibly induce diabetes mellitus. Here, we present five cases in which clozapine or olanzapine treatment were associated with de novo onset of diabetes mellitus. CASE REPORTS: Three out of the five cases had risk factors for diabetes and developed diabetes during the early phase of treatment with atypical antipsychotics. However, it took longer for the other two patients with no risk factor for diabetes to manifest symptoms of diabetes. In all of the cases, we were able to control their plasma glucose level within clinically tolerable range by applying diverse treatment modalities for diabetes mellitus and continue with antipsychotics treatment. CONCLUSION: These findings suggest that risk factors for diabetes such as family history of diabetes and baseline obesity may be related to development and time of onset of atypical antipsychotic drugs induced diabetes.

The Effects of Cyclosporin A on the Signal Transduction System in the Rat Brain / 대한정신약물학회지

The most important molecular mechanisms of intraneuronal signal transduction are those mediated by calcium and reversible protein phosphorylation. Although many studies pursued the activation of the protein kinases in the nervous system, there are only few reports focused on the protein phosphatases. In this article, the authors report the effects of cyclosporin A (CSA), an inhibitor of calcineurin, on the calcium signaling-related molecules such as ERKs, calmodulin-dependent kinase II (CaMKII) and CREB in the rat hippocampus. The authors also report the effects of cyclosporin A on the electroconvulsive shock (ECS)-induced seizure and the activation of ERKs. Calcineurin is a protein phosphatase that is abundant in the brain and regulated by calcium and calmodulin. It is proposed that calcineurin plays central roles in the synaptic plasticity and neuronal apoptosis. CSA (50 mg/kg) increased the phosphorylation of ERK, CaMKII and CREB. The treatment of of CSA increased the duration of tonic phase of seizure induced by ECS and augmented the phosphorylation of ERKs after ECS. These results suggested the protective role of calcineurin against the excessive electrical and molecular activities in the brain.

Developmental Changes in the Activation of Signal Transduction Pathway via JNK in Rat Hippocampus after Kainic Acid-Induced Seizure / 신경정신의학

OBJECTIVE: We observed the developmental pattern of activation of MAPK signal transduction pathways known to be activated by electroconvulsive shock(ECS) in young rat hippocampus after kainic acid(KA)-induced seizure. METHODS: We used the method of immunoblotting for examining the basal protein amount and basal level of phosphorylation of MAPK kinase(SAPK/ERK kinase -1, SEK-1), MAPK(c-Jun N terminal protein kinase, JNK), transcription factor(c-Jun) and immediate early gene proteins(Fos) in rat hippocampus at postnatal day 7, 14, and 21, respectively. We also examined the changes of phosphorylation of those proteins after kainic acid-induced seizure in the same way. RESULTS: The basal protein amounts of SEK-1, JNK, and c-Jun did not show age-dependent changes and basal level of phosphorylation of JNK and c-Jun remains unchanged throughout the early developmental period. The basal level of phosphorylation of SEK-1 was peaked at postnatal 7 days and then decreased with aging. After kainic acid-induced seizure, the change of phosphorylation of JNK was not observed but those of SEK-1 and c-Jun increased after postnatal day 14. The expression of Fos was observed at postnatal day 7 and also increased with aging. CONCLUSION: These results show that the MAPK signal transduction system in rat hippocampus matures in accordance with aging, but the process of maturation differs depending specific proteins. This study suggests the signal transduction cascade(SEK-1 - JNK - c-Jun - Fos) which is well established in cell line studies may not be applied to rat hipposcampus because we could not observe the activation of JNK after KA-induced seizure in young rat hippocampus.

A Study of Obsessive-Compulsive Symptoms in Schizophrenia: A Preliminary Study / 신경정신의학

OBJECTIVES: Obsessive-compulsive disorder (OCD) is highly prevalent in schizophrenia. And it has been suggested that schizophrenic patients with OCD have longer hospitalization, lower employment rate, and more severe psychopathology compared to those without OCD. The present study aimed to evaluate (1) the prevalence of OCD in subjects with schizophrenia, (2) the prognosis in schizophrenia with OCD, (3) the characteristics of OC symptoms, (4) the change of OC symptoms with selective serotonin reuptake inhibitor (SSRI) use. METHODS: We reviewed the medical records of 63 patients with schizophrenia and classified patients according to the existence of OC symptoms. And we evaluated the clinical and demographic data in 12 schizophrenic patients with OC symptoms and 51 schizophrenic patients without OC symptoms. RESULTS: Schizophrenic patients with OCD had more severe psychopathology (higher CGI) and poorer social functioning (lower GAF) than those without OCD. Social functoning estimated by the rate of employment showed near-significant differences between the two groups and the number of hospitalization was not significantly different. SSRI improved the OC symptoms in seven (70%) of the 10 SSRI users. CONCLUSION: Schizophrenic patients with OC symptoms had severe psychopathlogy and low social adaptation and needed antiobsessional therapy.

Drug Interaction in New Antipsychotics

Recently atypical antipsychotics have been used as first line agent in the treatment of schizophrenia, and also played a significant role in the treatment of many kinds of psychiatric disorders. The pharmacokinetic and pharmacodynamic properties of these newer antipsychotics are well know through preclinical and early clinical trials. However, it is important to note the limitations of the results due to its relatively short experience. Clozapine is eliminated principally by the hepatic P450 1A2 and 3A4 cytochrome enzymes. 1A2 inducers such as carbamazepine and smoking can reduce its half-life, while 1A2 inhibitors such as SSRIs especially fluvoxamine can increase its duration of action. Carbamazepine should be avoided in a patient on clozapine because of carbamazepine's potential effects on bone marrow. Benzodiazepines tend to increase the chances of sedation delirium and respiratory depression. Risperidone is metabolized to 9-hydroxyriperidone by the hepatic P450 2D6 cytochrome enzymes. Fluoxetine and paroxetine, 2D6 inhibitors interfere with metabolism, but 9-hydroxyrisperidone has similar biological activity as parental drug, so it has little affect on the outcome. Olanzapine shows minimal capacity to inhibit cytochrome P450 isoenzymes and shows minimal chance of drug interaction. It is eliminated principally by the hepatic P450 1A2 and 2D6 cytochrome enzymes.