Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins.

BACKGROUND: Childhood adverse experiences are known to induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear. Method We tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994-1995 cohort of families with twins. RESULTS: Bullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children's genetic makeup or their shared familial environments because of the study design. Bullied twins also showed increasing methylation levels between the age of 5 years, prior to bullying victimization, and the age of 10 years whereas no such increase was detected in non-bullied twins across time. Moreover, children with higher SERT methylation levels had blunted cortisol responses to stress. CONCLUSIONS: Our study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNA methylation at a specific cytosine-phosphate-guanine (CpG) site in the SERT promoter and HPA functioning and suggests that these two systems may be functionally associated.

Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system.

Despite the evidence of an association between depression and increased inflammatory markers, still little is known in relation to the most severe cases of the disorder i.e., those who fail to respond to antidepressants. We have assessed the cytokine profile and cortisol levels in 21 healthy controls (HC) and 19 medicated patients with depression with treatment-resistance (TRD) moderately ill. As an initial exploratory analysis, we have also related cytokine profile to the patient's clinical treatment outcome after an inpatient admission. Cytokine profile was measured in the serum by the Cytokine Array I kit (Randox). Plasma cortisol was carried out using a commercially available for the IMMULITE system. When compared to healthy controls, depressed patients had higher levels of cortisol, IL-6, IL-10, but lower levels of IL-4 and VEGF. Our exploratory analysis showed subjects who did not go on to respond to the inpatient admission treatment package had lower levels of MCP-1, and a trend toward lower levels of VEGF. Taking together, these data suggest that lack of clinical therapeutic benefit of antidepressants is associated with overall activation of the inflammatory system.

Psychological and physiological effects of caring for patients with treatment-resistant depression.

BACKGROUND: Carers of patients with psychiatric disorders show high levels of anxiety and depression, possibly mediated through disruption of the hypothalamo-pituitary-adrenal (HPA) axis. Among carers of patients with treatment-resistant depression (TRD), we set out to determine the psychological and physiological (HPA axis) consequences of caring, and the association of these consequences with long-term outcome in patients. METHOD: Thirty-five informal carers of patients with severe TRD requiring in-patient treatment were recruited and compared with 23 controls. HPA-axis activity was assessed by measuring post-awaking salivary cortisol. The Involvement Evaluation Questionnaire (IEQ) and the General Health Questionnaire-12 (GHQ-12) were administered to measure carer burden and psychiatric caseness respectively. Independent t tests were used to compare differences between carers and controls and a linear regression model was used to determine the association of post-awakening cortisol with carer status while controlling for confounding variables. Data on long-term patient outcome (12 to 83 months), measured using the Hamilton Depression Rating Scale (HAMD), were also obtained and linear regression was used to determine the association between cortisol output in carers and remission status in patients. RESULTS: Carers experienced high carer burden and high psychiatric caseness. Carers showed reduced cortisol output after awakening, calculated as the area under the curve with respect to ground (AUCg), which remained significant after controlling for potential confounders. In a linear regression model, non-remission in patients was associated with reduced cortisol output in carers. CONCLUSIONS: Caring for patients with TRD is associated with adverse psychological and physiological changes suggesting hypocortisolism post-awakening. These changes are associated with poor patient outcome.

Changes in the maternal hypothalamic-pituitary-adrenal axis during the early puerperium may be related to the postpartum 'blues'.

Most women experience time-limited and specific mood changes in the days after birth known as the maternity blues (Blues). The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes gradual changes during pregnancy because of an increasing production of placental corticotrophin-releasing hormone (CRH). The abrupt withdrawal of placental CRH at birth results in a re-equilibration of the maternal HPA axis in the days post-delivery. These changes may be involved in the aetiology of the Blues given the central role of the HPA axis in the aetiology of mood disorders in general, and in perinatal depression in particular. We aimed to test the novel hypothesis that the experience of the Blues may be related to increased secretion of hypothalamic adrenocorticotrophic hormone (ACTH) secretagogue peptides, after the reduction in negative-feedback inhibition on the maternal hypothalamus caused by withdrawal of placental CRH. We therefore examined hormonal changes in the HPA axis in the days after delivery in relation to daily mood changes: our specific prediction was that mood changes would parallel ACTH levels, reflecting increased hypothalamic peptide secretion. Blood concentrations of CRH, ACTH, cortisol, progesterone and oestriol were measured in 70 healthy women during the third trimester of pregnancy, and on days 1-6 post-delivery. Blues scores were evaluated during the postpartum days. Oestriol, progesterone and CRH levels fell rapidly from pregnancy up to day 6, whereas cortisol levels fell modestly. ACTH concentrations declined from pregnancy to day 3 post-delivery and thereafter increased up to day 6. Blues scores increased, peaking on day 5, and were positively correlated with ACTH; and negatively correlated with oestriol levels during the postpartum days, and with the reduction in CRH concentrations from pregnancy. These findings give indirect support to the hypothesis that the 'reactivation' of hypothalamic ACTH secretagogue peptides may be involved in the aetiology of the Blues.

Increased pituitary-adrenal activation and shortened gestation in a sample of depressed pregnant women: a pilot study.

BACKGROUND: Major depression (MD) is frequently accompanied by a relatively increased production of the stress hormone cortisol. During pregnancy corticotrophin releasing hormone (CRH) is secreted from the placenta and critically high levels of CRH are one of the key triggers for parturition. Maternal cortisol promotes the secretion of placental CRH. In this study, we examined the hypothesis that women suffering with MD in pregnancy would have relatively increased cortisol secretion, a time-advanced rise in placental CRH production and an earlier delivery of the baby. METHODS: A group of medication-free pregnant women, free of know obstetric and medical complications, with (n=27) and without (n=38) MD were recruited. Blood concentrations of CRH, adrenocorticotrophic hormone (ACTH) and diurnal salivary cortisol concentrations were measured at fixed time points. RESULTS: Maternal cortisol concentrations were highly correlated with placental CRH secretion for the entire group. Second trimester CRH concentrations and mean evening salivary cortisol concentrations were significantly higher in the depressed women. Although pregnancy length was shorter in the depressed women there were no statistical relationships between the stress hormone measures and pregnancy length. LIMITATIONS: The sample size was small and highly selected. CONCLUSIONS: These findings suggest that depressed pregnant women hypersecrete cortisol in a diurnal pattern similar to that typical of MD, and that this leads to a time-advanced rise in placental CRH secretion. Factors other than this stress-delivery mechanism may be contributing to the shortened pregnancy length in depressed women.

Sulphoxide metabolites of thioridazine in man.

Chromatograms of urine extracts from patients taking thioridazine contain several different sulphoxide metabolites. Some of these have not hitherto been described or identified. Two of the unknown metabolites appear, from chemical tests and mass spectrometry, to be isomers of the already known thioridazine ring-sulphoxide and sulphoridazine ring-sulphoxide from which they can be produced by treatment with trifluoroacetic anhydride. Two others appear, by similar identification tests and i.r. analysis, to be lactams of mesoridazine ring-sulphoxide and of sulphoridazine ring-sulphoxide.

Phenolic metabolites of thioridazine in man.

After oral administration of thioridazine or mesoridazine to man, faecal extracts contained mainly unconjugated 7-hydroxy-thioridazine and its demethylated analogue, together with some 3-hydroxy-thioridazine, and 7-hydroxy derivatives of sulphoridazine and desmethyl sulphoridazine. In contrast, urine contained free 7-hydroxy-mesoridazine, and no free 7-hydroxy-thioridazine was detectable. Conjugates of all these phenols were also found. After oral sulphoridazine administration (thioridazine side-chain sulphone), urine contained mainly 7-hydroxy-sulphoridazine and faeces both 7-hydroxy-sulphoridazine and its desmethyl analogue. Sulphoridazine metabolism is therefore much simpler than that of thioridazine. This different elimination pattern in faeces and urine may be due to reduction of sulphoxides but not sulphones by intestinal bacteria.

Determination of left ventricular residual function by analysis of post-extrasystolic beat in mitral stenosis.

Residual function of the left ventricle was assessed in 25 patients with mitral stenosis and a normal left ventriculogram. The post-extrasystolic beat (R2) in sinus rhythm (nine patients) and the first beat after an early beat (R2) in atrial fibrillation (16 patients) were analysed angiocardiographically. Five subjects with a normal heart (controls) were also studied. The results are expressed as percentage changes in left ventricular contractility from the beat preceding the extra beat (R1) to the beat R2. In the control group the mean changes from R1 to R2 were: end diastolic volume +68.3% (increase), end systolic volume -21.7% (decrease), ejection fraction +36.2%, mean systolic ejection rate +22.1%, and mean velocity of circumferential fibre shortening +31%. A significant increase in proportional systolic shortening of all left ventricular axes was found in R2 compared with R1. In five patients with sinus rhythm and nine with atrial fibrillation the results fell within the normal range. In the remaining patients the beat R2 indicated signs of poor left ventricular function. The mean changes from R1 to R2 in the patients with sinus rhythm and those with atrial fibrillation were respectively: end diastolic volume +47.8% and +36.6%, end systolic volume +20% and +27%, ejection fraction +12.5% and +6.2%, mean systolic ejection rate -23.3% and -30.2%, and mean velocity of circumferential fibre shortening -25.5% and -39.2%. The increase in the left ventricular axial systolic shortening was not significant. Thus analysing a post-extrasystolic beat in sinus rhythm of the beat following an early beat with a long diastole in atrial fibrillation is a valuable method of determining the residual function in patients with mitral stenosis who have a normal left ventriculogram in basic rhythm.

A pilot of plasma thioridazine and metabolites in chronically treated patients.

Plasma concentrations of thioridazine, mesoridazine, sulphoridazine and thioridazine ring sulphoxide have been measured individually by specific gas-liquid chromatographic (GLC) methods, and collectively by a radio-receptor assay, in 16 elderly in-patients during chronic treatment. The sulphoridazine level was above 0.135 microgram/ml in 5 out of 6 symptomatically well-controlled patients, and below this level in 9 out of 10 who were poorly controlled. No such division was so clear for the other substances measured. A new assay for the total dopamine receptor-blocking activity of the plasma correlated highly at lower levels with the sum of drug plus metabolites obtained by GLC, but exceeded the sum at higher values. Both sulphoridazine and neuroleptic levels need further study.