Correlation between Serum 25-Hydroxyvitamin D Level and Depression among Korean Women with Secondary Amenorrhea: A Cross-Sectional Observational Study.

Vitamin D deficiency is considered a major public health problem worldwide and has been reported as having an association with depression. However, studies on the association between vitamin D deficiency and depressive symptoms in secondary amenorrhea (SA) patients are still scarce. This study examined the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and depressive symptoms among Korean women with SA. In this cross-sectional observational study, 78 patients with SA were initially recruited. Clinical and biochemical parameters, including serum 25(OH)D level, were measured. Data from 63 SA patients who met the study inclusion criteria and completed psychiatric assessments were finally analyzed. We analyzed their association with depression using a hierarchical regression model. The average serum 25(OH)D level was 34.40 ± 24.02 ng/mL, and 41.3% of the women with SA were vitamin D-deficient (<20 ng/mL). The total score of the Korean version of the Hamilton Depression Rating Scale (K-HDRS) was negatively related to serum 25(OH)D levels, free testosterone, and serum anti-Müllerian hormone (AMH) after adjusting for age and BMI (r = −0.450, p < 0.001; r = −0.258, p = 0.045; and r = −0.339, p = 0.006, respectively). Serum 25(OH)D levels and AMH levels were the most powerful predictors of depressive severity when using the K-HDRS in SA patients (ß = −0.39, p < 0.005; ß = −0.42, p < 0.005, respectively). This study showed that low serum 25(OH)D levels were associated with the severity of depressive symptoms in SA patients. This observation suggests that the evaluation of vitamin D deficiency for the risk of depression may be necessary in patients with SA.

Dyskinesia is most centrally situated in an estimated network of extrapyramidal syndrome in Asian patients with schizophrenia: findings from research on Asian psychotropic prescription patterns for antipsychotics.

BACKGROUND: Network analysis provides a new viewpoint that explicates intertwined and interrelated symptoms into dynamic causal architectures of symptom clusters. This is a process called 'symptomics' and is concurrently applied to various areas of symptomatology. AIMS: Using the data from Research on Asian Psychotropic Prescription Patterns for Antipsychotics (REAP-AP), we aimed to estimate a network model of extrapyramidal syndrome in patients with schizophrenia. METHODS: Using data from REAP-AP, extrapyramidal symptoms of 1046 Asian patients with schizophrenia were evaluated using the nine items of the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The estimated network of the ordered-categorical DIEPSS items consisted of nodes (symptoms) and edges (interconnections). A community detection algorithm was also used to identify distinctive symptom clusters, and correlation stability coefficients were used to evaluate the centrality stability. RESULTS: An interpretable level of node strength centrality was ensured with a correlation coefficient. An estimated network of extrapyramidal syndrome showed that 26 (72.2%) of all possible 35 edges were estimated to be greater than zero. Dyskinesia was most centrally situated within the estimated network. In addition, earlier antipsychotic-induced extrapyramidal symptoms were divided into three distinctive clusters - extrapyramidal syndrome without parkinsonism, postural instability and gait difficulty-dominant parkinsonism, and tremor-dominant parkinsonism. CONCLUSIONS: Our findings showed that dyskinesia is the most central domain in an estimated network structure of extrapyramidal syndrome in Asian patients with schizophrenia. These findings are consistent with the speculation that acute dystonia, akathisia, and parkinsonism could be the risk factors of tardive dyskinesia.

Serum vitamin D levels and ovarian reserve markers in secondary amenorrhea patients: Is there a link?

OBJECTIVE: To investigate whether serum 25-hydroxyvitamin D [25(OH)D] level is associated with ovarian reserve markers in secondary amenorrhea (SA) patients. METHODS: Sixty-three women diagnosed with SA were recruited during 12 months from the initiation of this prospective observational study. Serum 25(OH)D levels, serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were estimated in study participants and ovarian reserve markers were compared between participants with vitamin D deficiency and those with normal vitamin D levels. RESULTS: Of the 63 participants, 27 (42.9%) were vitamin D deficient (<20 ng/mL) and 36 (57.1%) had normal vitamin D levels. The mean AMH levels and AFC were 10.86±8.94 µ/L and 15.23±7.65 in the vitamin D deficient group, and 7.24±5.62 µ/L and 12.30±6.95 in the normal vitamin D group. Univariate and multivariate linear regression analysis of log10 transformed AMH and AFC with serum 25(OH)D adjusted for age and body mass index confirmed no association between vitamin D levels and AMH levels or AFC. There was also no correlation between serum 25(OH)D and AMH levels or AFC in all participants. However, participants with vitamin D deficiency had an increased chance of having polycystic ovarian syndrome (PCOS) as cause of SA than those with normal vitamin D levels (adjusted odds ratio, 7.559; 95% confidence interval, 1.28-44.65; P=0.026) after adjustment for clinical factors by logistic regression model. CONCLUSION: There was no correlation between serum 25(OH)D levels and ovarian reserve markers in SA patients, but vitamin D deficiency may be linked to PCOS patients.

Comparison of the risk factors of Korean adolescent suicide residing in high suicidal regions versus those in low suicidal regions.

BACKGROUND: The suicide rate of the youth in South Korea has been increasing, and suicide of the youth still has been the most common cause of death since 2007. We aimed to determine the trends and the regional risk factors of youth suicide in South Korea from 2001 to 2010. SUBJECTS AND METHODS: We used the data from the National Statistical Office to calculate the standardized suicide rates and various regional data including population census, employment, and labor. To calculate the effect of individual risk factors, we used the data from the fourth Korean Youth Risk Behavior Web-based Survey (KYRBWS-VI). Conditional autoregressive model for regional standardized mortality ratio (SMR) using inter-regional spatial information was fitted. RESULTS: Suicide rates of adolescents aged 12 to 18 was from 3.5 per 100,000 people in 2001 and 5.3 per 100,000 in 2010. There were no significant gender difference in suicide rates, however, the number of suicides among adolescents aged 15-18 accounted for four times than those of adolescents ages 12-14. High proportion of late adolescents, higher number of recipients of national basic livelihood, and higher number of adolescents who treated with depression were related to elevated suicide rate of adolescent. Total sleep time of adolescents and regional unemployment rate were negatively associated with the suicide risk of respective regions. CONCLUSIONS: Age distribution, economic status, total sleep time, and the number of adolescent patients with depression were different between those in low and in high adolescent suicidal regions in Korea. Our findings suggest that preferential appliance of adolescent suicide prevention program for regions by considering those factors may be important steps to reduce adolescent suicide in Korea.

Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats.

Recent studies have shown that antipsychotic drugs have epigenetic effects. However, the effects of antipsychotic drugs on histone modification remain unclear. Therefore, we investigated the effects of antipsychotic drugs on the epigenetic modification of the BDNF gene in the rat hippocampus. Rats were subjected to chronic restraint stress (6 h/d for 21 d) and then were administered with either olanzapine (2 mg/kg) or haloperidol (1 mg/kg). The levels of histone H3 acetylation and MeCP2 binding at BDNF promoter IV were assessed with chromatin immunoprecipitation assays. The mRNA levels of total BDNF with exon IV, HDAC5, DNMT1, and DNMT3a were assessed with a quantitative RT-PCR procedure. Chronic restraint stress resulted in the downregulation of total and exon IV BDNF mRNA levels and a decrease in histone H3 acetylation and an increase in MeCP2 binding at BDNF promoter IV. Furthermore, there were robust increases in the expression of HDAC5 and DNMTs. Olanzapine administration largely prevented these changes. The administration of haloperidol had no effect. These findings suggest that the antipsychotic drug olanzapine induced histone modification of BDNF gene expression in the hippocampus and that these epigenetic alterations may represent one of the mechanisms underlying the actions of antipsychotic drugs.

Epigenetic modification of glucocorticoid receptor promoter I7 in maternally separated and restraint-stressed rats.

Glucocorticoid receptor (GR) promoter I7 is susceptible to epigenetic changes induced by environmental influences. Early life stress (ELS) has a persistent impact on GR expression, as well as behavior, in adult rodents via epigenetic changes of GR promoter I7. Moreover, various stressors can induce histone modifications in this region during adulthood. Thus, the present study aimed to investigate whether maternally separated (MS) rats exposed to chronic restraint stress (RS) would exhibit histone modifications of GR promoter I7 in the hippocampus. Rats were subjected to MS (3h per day) on postnatal days (PND) 1-21. Then, during adulthood (PND 56-77), the rats were exposed to RS (2h per day) followed by treatment with escitalopram (10mg/kg). The MS and RS groups exhibited significant decreases in total and exon I7 GR mRNA levels and the combination of MS and RS exerted a greater effect on these mRNA levels than either MS or RS alone. Additionally, both the MS and RS groups showed significant reductions in histone H3 acetylation at GR promoter I7 and the combination of MS and RS had a greater effect than did either MS or RS alone. Chronic escitalopram treatment ameliorated these changes. The present results indicate that postnatal MS and adult RS influence GR expression through histone modification at GR promoter I7, and that the combination of the two stressors potentiates these changes. Furthermore, epigenetic mechanisms are involved in escitalopram action.

Tianeptine induces mTORC1 activation in rat hippocampal neurons under toxic conditions.

RATIONALE: Recent studies have demonstrated that mTORC1 activation may be related to antidepressant action. However, the relationship between mTORC1 signaling activation and currently prescribed antidepressants remains unclear. OBJECTIVE: The aim of the present study was to determine whether alterations in mTORC1 signaling are observable following treatment with tianeptine under toxic conditions induced by B27 deprivation. Additionally, we investigated whether this drug affects synaptic proteins, neurite outgrowth, and spine density via mTORC1 signaling. METHODS: Using Western blotting, we measured the phosphorylation levels of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK in rat primary hippocampal neurons. Changes in BDNF, dendritic outgrowth, spine density, and synaptic proteins (PSD-95, synaptophysin, and GluR1) were measured. RESULTS: Tianeptine significantly increased the phosphorylation of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK. The increase in mTOR phosphorylation was blocked by the PI3K, MEK, and mTORC1 inhibitors. Tianeptine increased BDNF, dendritic outgrowth, spine density, and synaptic proteins; all of these effects were blocked by the mTORC1 inhibitor. CONCLUSIONS: In this study, we demonstrated that tianeptine activates the mTORC1 signaling pathway and increases dendritic outgrowth, spine density, and synaptic proteins through mTORC1 signaling under toxic conditions in rat primary hippocampal neurons.

p11 mediates the BDNF-protective effects in dendritic outgrowth and spine formation in B27-deprived primary hippocampal cells.

BACKGROUND: p11 (S100A10) is a key regulator of depression-like behaviors and antidepressant drug response in rodent models. Recent studies suggest that p11 mediates the behavioral antidepressant action of brain-derived neurotrophic factor (BDNF) in rodents. BDNF improves neural plasticity, which is linked to the cellular actions of antidepressant drugs. In the present study, we investigated whether p11 regulated BDNF action on neural plasticity in vitro. METHODS: We generated primary hippocampal cultures. p11 expression, total dendritic length, and spine density were investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. RESULTS: B27 deprivation significantly decreased p11 expression. Treatment with BDNF significantly prevented the B27 deprivation-induced decrease in p11 levels in a concentration-dependent manner, whereas these concentrations had no effect on control cultures. B27 deprivation significantly reduced the total length of hippocampal dendrites and spine density. BDNF increased the total dendritic length and spine density in conditions with or without B27. Furthermore, p11 knockdown through small interfering RNA (siRNA) transfection blocked these effects. The overexpression of p11 in B27-deprived cells increased the total dendritic length and spine density, and treatment with BDNF potentiated these effects. LIMITATION: This study should be confirmed in animal models of depression. CONCLUSION: Taken together, our data suggest that BDNF-induced improvement in neural plasticity may depend on the regulation of p11 in hippocampal cells with B27 deprivation. These results provide evidence to strengthen the theoretical basis of a role for p11 in BDNF-induced antidepressant action.

Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus.

Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action.

Positive association between serious psychiatric outcomes and complications of diabetes mellitus in patients with depressive disorders.

OBJECTIVES: Depression and diabetes are closely biologically and behaviorally intertwined. We examined the impact of comorbid diabetes mellitus on the incidence of serious psychiatric outcomes among patients with depression. METHODS: We used claims data from the Korean Health Insurance Review & Assessment Service database of patients who were diagnosed with depression within one year of an index prescription for antidepressants between January 2007 and June 2008. We investigated the association between the comorbidity of diabetes mellitus and serious psychiatric outcomes of depression, such as psychiatric hospitalization, psychiatric emergency room visits, and suicide attempts. RESULTS: Among 200,936 patients with depression, 74,160 (36.9%) had diabetes mellitus, including 57,418 (28.6%) with complications. The incidence of serious psychiatric outcomes was 3.3% in patients with depression without diabetes and 6.7% in patients with depression and diabetes mellitus. Patients with depression and diabetes mellitus complications showed higher rates of serious outcomes than that did those without diabetes mellitus complications (odds ratio, 1.19; 95% confidence interval, 1.11-1.13). Similarly, depressed patients with micro and macrovascular diabetic complications were more likely to experience serious outcomes than those without diabetes mellitus complications (odds ratio, 2.2; 95% confidence interval, 2.07-2.34). CONCLUSIONS: Our results showed that comorbid diabetes mellitus can increase the risk of serious outcomes of depression, such as suicide and hospitalization, and thus may alter the antidepressants prescription patterns and healthcare service use among patients with depressive disorders.

Twelve-month prevalence and predictors of self-reported suicidal ideation and suicide attempt among Korean adolescents in a web-based nationwide survey.

OBJECTIVE: The suicide rate in South Korea was the highest among the Organisation for Economic Co-operation and Development (OECD) countries in 2011. Although the suicide rate in adolescents is lower than that of adults and is reported to be decreasing in young males in some countries, it has consistently increased in recent years in South Korea. We aimed to determine the prevalence, pattern, and predictors of suicidal ideation and attempt in the past 12 months. METHODS: A total sample of 72,623 adolescents aged 12-18 years who responded to a web-based anonymous self-reported survey between September and October 2010 was used for the analysis. RESULTS: The suicidal ideation and suicide attempt rates were 19.1% and 4.9%, respectively. Being female, having a poor perceived socioeconomic status and a poor perceived academic performance, subjective feelings of depression, cigarette smoking, alcohol use, perceived general medical health, and experiences of any involvement with sexual intercourse were the contributing factors that predicted elevated risks for suicidal ideation and suicide attempt. In contrast to previous reports in other countries, the suicide attempt rate in Korean female adolescents peaked at age 13 years, and there were no differences in suicidal ideation in females by age. There were no differences in both suicidal ideation and attempt rates in males by age. CONCLUSION: A multidisciplinary approach that takes into consideration the characteristics of Korean adolescents with suicidal ideation or suicide attempt is warranted for developing prevention and treatment programs.

Effect of aripiprazole on cognitive function and hyperprolactinemia in patients with schizophrenia treated with risperidone.

OBJECTIVE: This study aimed to assess the efficacy of aripiprazole for the management of cognitive impairments and hyperprolactinemia in patients with schizophrenia on a stable dose of risperidone. METHODS: Thirty-five subjects stabilized on risperidone (3-6 mg/day) for a minimum of 3 months were enrolled in a double-blind, placebo-controlled phase for 12 weeks and an open-label phase for another 12 weeks. Subjects were randomly assigned to receive 10 mg/day aripiprazole (n=17) or placebo (n=18). Over the following 12 weeks, the the aripiprazole group received a flexible dose of aripiprazole while tapering risperidone. At baseline, week 12, and week 24, subjects were evaluated using the Positive and Negative Syndrome Scale (PANSS), Extrapyramidal Syndrome Rating Scale (ESRS), and standardized neuropsychological assessments. Serum prolactin levels were checked at baseline, week 1, week 2, and week 24. RESULTS: The mean change in total PANSS and cognitive function test scores between baseline and endpoint were similar in the aripiprazole and placebo groups. Scores on the ESRS and negative subscale of PANSS differed significantly between groups in both phases of the study (p<0.05), indicating a positive effect of aripiprazole. Compared with placebo, aripiprazole significantly reduced mean baseline serum prolactin levels within 1 week (p=0.015). CONCLUSION: Adjunctive treatment with and switching to aripiprazole were not associated with improved cognitive function in patients with schizophrenia receiving risperidone; however, aripiprazole treatment decreased negative symptoms and risperidone-induced motor side effects and lowered serum prolactin levels.

Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study.

OBJECTIVE: To investigate the effects of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on cognitive impairments in patients with chronic schizophrenia. METHODS: A 12-week, placebo-controlled trial was conducted to determine the effectiveness of memantine as an adjunctive treatment with conventional antipsychotic medications in 26 patients with chronic schizophrenia. The subjects were evaluated with the Korean version of the Mini-Mental State Examination (K-MMSE), the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), and a standard neuropsychological screening test. RESULTS: Memantine treatment was not associated with significantly improved cognitive test scores compared with the placebo control treatment. An improvement in the scores on the PANSS negative subscale was noted with memantine, but it was not significant. CONCLUSION: Adjunctive memantine treatment did not improve cognitive functioning or affect psychopathology in patients with chronic schizophrenia in the present study. Memantine, however, was tolerated well and did not exacerbate positive symptoms in patients with chronic schizophrenia.

Determinants for heart rate variability in a normal Korean population.

This study examined the normal ranges and the determinants for various parameters of the short-term heart rate variability (HRV) measurements in a large Korean sample of healthy people. HRV measurements were obtained in 2,748 healthy men and 735 healthy women 18-65 yr of age. The mean total power (TP), low frequency (LF), high frequency (HF), and LF/HF ratio were 1,358.9 ± 1,840.8 ms(2), 417.3 ± 807.6 ms(2), 254.1 ± 414.1 ms(2), and 2.4 ± 20.9 ms(2) in the frequency-domain spectral analysis. The mean standard deviation of the normal-to-normal (NN) interval (SDNN) and the square root of the mean squared differences of successive NN intervals (RMSSD) were 39.6 ± 22.1 ms and 29.7 ± 18.1 ms in the time-domain analysis. The female subjects had significantly higher SDNN, RMSSD, and HF values than the male subjects. After controlling for age, there was no statistically significant difference in the SDNN. Quantile regression analysis showed that age and mean heart rate had a significant impact on short-term HRV measurement. Given that both clinicians and researchers are increasingly relying on short-term HRV assessment in measuring stress, our work suggests that age and gender should be considered as independent determinants for HRV.