Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder.

Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearson's correlation: r=-0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=-0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD.

Brain-derived neurotrophic factor gene polymorphisms and mirtazapine responses in Koreans with major depression.

Brain-derived neurotrophic factor (BDNF) is a candidate molecule for influencing the clinical response to antidepressant treatment. The aims of this study were to determine the relationship between the Val66Met polymorphism in the BDNF gene and the response to mirtazapine in 243 Korean subjects with major depressive disorder (MDD). The reduction in the Hamilton Depression score over the 8-week treatment period was not influenced by BDNF V66M genotypes. A marginal effect of genotype on somatic anxiety score was observed at baseline (P = 0.047 in the dominant model). However, genotype-time interaction had no effect on somatic anxiety score after the 8-week a treatment period. Plasma BDNF levels tended to increase during mirtazapine treatment, although without statistical significance (P = 0.055). After 8 weeks of mirtazapine treatment, plasma BDNF levels were higher in Met allele homozygotes (1499.7 ± 370.6 ng/mL) than in Val allele carriers (649.7 ± 158.5 ng/mL, P = 0.049). Our results do not support the hypothesis that the Val66Met promoter polymorphism in the BDNF gene influences the therapeutic response to mirtazapine in Korean MDD patients. However, our data indicate that this polymorphism results in increased plasma BDNF after mirtazapine treatment.

Changes in premenstrual symptoms in women with schizophrenia: a prospective study.

OBJECTIVE: We investigated whether the psychiatric symptoms and clinical features of schizophrenia change during the premenstrual phase in female patients. METHODS: We observed 30 female schizophrenic inpatients over one menstrual cycle. All subjects met DSM-IV criteria for schizophrenia, and all had a regular menstrual cycle. All subjects completed the Daily Rating Form (DRF) every evening, and one psychiatrist rated the subjects (using the Brief Psychiatric Rating Scale [BPRS]) once during each of the three menstrual phases (premenstrual, menstrual, and postmenstrual). Serum levels of estradiol (E2) and progesterone were measured on the fifth to seventh day of both the premenstrual and postmenstrual phases. Data from the 24 subjects who completed the DRF correctly and completely were used for statistical analysis. RESULTS: The mean total BPRS score for the 24 subjects was highest in the premenstrual phase and lowest in the postmenstrual phase, and a statistically significant difference was found among the three menstrual phases. Mean subtotal BPRS scores showed statistically significant differences among the three menstrual phases in anxiety/depression and withdrawal/retardation, but not in the psychotic symptom subscales. Mean serum E2 level showed a trend of increasing from the premenstrual phase to the postmenstrual phase. However, there was no significant correlation between DeltaBPRS and DeltaE2. When the criterion of 30% change was applied, the DRF items of depressed mood, anxious/nervous/restless, hostile/aggressive, and less/impaired work showed high frequencies of change in the premenstrual phase. Somatic items of abdominal pain, breast pain, and headache showed significant change with the 30% change rule on the DRF. On both the BPRS and DRF scores, premenstrual change of affective and behavioral symptoms was prominent, whereas the change of psychotic symptoms was minimal on the BPRS. In addition, in the premenstrual phase, there was a statistically significant correlation between the total BPRS score and the mean total DRF score. There was no correlation between premenstrual change in symptoms and hormonal levels of E2, progesterone, and the estradiol/progesterone (E/P) ratio. CONCLUSIONS: The findings of this study suggest that premenstrual exacerbation of schizophrenic symptoms in female patients may not be a worsening of the schizophrenic symptoms but a concurrence of affective, behavioral, and somatic symptoms.

Possible acceleration of age effects on cognition following menopause.

Many cognitive functions have been shown to deteriorate with age. Because of the importance of the menopause as a milestone in the life cycles of women, we examined whether the aging-over-time process in some cognitive functions differs between women of reproductive age and postmenopausal women. It is demonstrated here that in some cognitive tests, including driving simulation, reaction time and some visuospatial tests, there is a significant acceleration in deterioration of functioning following menopause. It is suggested that this acceleration might be associated with the lack of gonadal hormones or other reproduction-related factors which may play a protective role against age-related deterioration in some cognitive functions in women.

The significance of calcific valvular heart disease in Tc-99m pyrophosphate myocardial infarction scanning: radiographic, scintigraphic, and pathological correlation.

Technetium-99m pyrophosphate (PPi) is currently considered the best scanning agent for the diagnosis of acute myocardial infarction. False-positive scans have been reported in association with unstable angina, alcoholic cardiomyopathy, and ventricular aneurysms. In this study, 86% of patients (12/14) with either calcific aortic or mitral valvular heart disease had positive PPi cardiac scintiscans and the location of the PPi uptake was limited to the calcific valve in all (9/9) of the patients who underwent valve replacement surgery. Six patients with valvular disease without radiologic evidence of calcium had negative PPi heart images. Three of these patients had surgical valve replacement, and in none was there increased uptake in the resected valve. Seventy-five percent of the patients with calcified aortic valves had localization of the PPi activity to the area of the aortic valve, whereas 50% of the patients with calcified mitral valves showed a diffuse pattern of uptake on the cardiac image. In vitro demonstration of increased radioactivity in surgically removed cardiac valves warrants the conclusion that Tc-99m PPi is taken up by calcified heart valves. We conclude that while PPi heart scanning is a sensitive indicator of acute myocardial infarction, false-positive scans can occur in the presence of calcific valvular disease, due to localization of PPi in the calcified portion of the valve.