Internet-based interdisciplinary therapeutic group (Grupo Interdisciplinar Online, GIO) for perinatal anxiety and depression-a randomized pilot study during COVID-19.

Early interventions may promote reductions in mothers' anxiety-depression (AD) symptoms and improvements in their offspring. This longitudinal randomized research was conducted to assess the effects of interdisciplinary online therapeutic groups (GIO) in at-risk mothers and babies during the COVID-19 pandemic in a disadvantaged neighborhood in Barcelona (Spain). A total of 135 babies were born from March 2020 to June 2021 in a primary healthcare center of Barcelona (Spain). Pregnant woman and new mothers were screened for AD symptomatology through EPDS and STAI questionnaires. Seventy-two of them met high-risk criteria for AD and were included in the study. They were randomly assigned into the two groups of the study: 40 participants were assigned to GIO, the therapeutic group (TG), while 32 of them were assigned to the control group (CG) and received treatment as usual. The course of the mothers' symptomatology was assessed, as well as the baby's development at 6 months old in a blind pediatric follow-up. No differences were found in AD between both groups before the intervention. However, we obtained a significant decrease in AD symptomatology (EPDS p < .001; STAI state p = .015 and STAI trait p < .001at 6 months of life) after the intervention in the TG compared to the CG. Pediatric follow-up at 6 months demonstrated significant differences between groups in babies' development assessment (manipulation p = .003; language p < .001; sociability p < .001). The GIO helped to ensure healthy development of the baby and reduction of the mothers' depressive-anxiety symptomatology.

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3.

BACKGROUND: Maternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression. METHOD: A diagnosis of depression during pregnancy was recorded from Manchester cohort participants' medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression. RESULTS: In a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively). CONCLUSIONS: This study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.

Prenatal stress and neurodevelopment of the child: focus on the HPA axis and role of the placenta.

Recent human studies have shown that a wide variety of prenatal stressors, from anxiety and partner relationship problems, to natural disasters, increase the risk for a diverse range of adverse neurodevelopmental outcomes in the child. These include impaired cognitive development and behavioral problems, autism and schizophrenia. However, many questions remain about the underlying processes. Much of the research, based on animal studies, has focussed on the maternal HPA axis, with mixed results. Maternal stress or anxiety during pregnancy has been found to be weakly associated with raised maternal cortisol, if at all. The placenta may be a more promising programming vector, because it controls fetal exposure to the maternal environment. Animal studies indicate that prenatal stress can affect the activity of the placental barrier enzyme 11-betaHSD2, which metabolises cortisol. We review the evidence for a similar mechanism in humans and how maternal stress may cause other changes in the placenta which affect fetal neurodevelopment.

Salivary alpha-amylase stability, diurnal profile and lack of response to the cold hand test in young women.

Salivary cortisol measurement has proved useful for the non-invasive study of the hypothalamic-pituitary-adrenocortical axis, and salivary alpha-amylase has been suggested as a comparable marker for the sympathetic system. Despite some studies showing an increase in salivary alpha-amylase after challenges that stimulate the sympathetic nervous system, questions remain about interpretation. The aims of this study were to explore the stability of salivary alpha-amylase, its diurnal profile, response to the cold hand test, and correlation with cortisol. Salivary alpha-amylase was stable following 5 days at room temperature, and five freeze-thaw cycles. Its diurnal profile was opposite to that of cortisol. There was no salivary alpha-amylase response to the cold hand stress test, in the morning (11am) or afternoon (3pm), unlike cortisol which showed a response in the afternoon in the same samples. There was no correlation between salivary alpha-amylase and cortisol at any time. In conclusion, salivary alpha-amylase is stable to a range of conditions. Its diurnal pattern is compatible with sympathetic stimulation. Lack of response to the cold hand test suggests that secretion of salivary alpha-amylase is controlled by mechanisms more complex than sympathetic regulation alone.

Maternal antenatal mood and child development: an exploratory study of treatment effects on child outcomes up to 5 years.

Effective treatment of maternal antenatal depression may ameliorate adverse neurodevelopmental outcomes in offspring. We performed two follow-up rounds of children at age 2 and age 5 whose mothers had received either specialized cognitive-behavioural therapy or routine care for depression while pregnant. Of the original cohort of 54 women, renewed consent was given by 28 women for 2-year follow-up and by 24 women for 5-year follow-up. Child assessments at the 2-year follow-up included the Parenting Stress Index (PSI), Bayley Scales of Infant Development (BSID-III) and the Child Behaviour Checklist (CBCL). The 5-year follow-up included the Wechsler Preschool and Primary Scales of Intelligence (WPPSI-III) and again the CBCL. Treatment during pregnancy showed significant benefits for children's development at age 2, but not at age 5. At 2 years, intervention effects were found with lower scores on the PSI Total score, Parent Domain and Child domain (d=1.44, 1.47, 0.96 respectively). A non-significant trend favoured the intervention group on most subscales of the CBCL and the BSID-III (most notably motor development: d =0.52). In contrast, at 5-year follow-up, no intervention effects were found. Also, irrespective of treatment allocation, higher depression or anxiety during pregnancy was associated with higher CBCL and lower WPPSI-III scores at 5 years. This is one of the first controlled studies to evaluate the long-term effect of antenatal depression treatment on infant neurodevelopmental outcomes, showing some benefit. Nevertheless, caution should be taken interpreting the results because of a small sample size, and larger studies are warranted.

Quality of child-parent attachment moderates the impact of antenatal stress on child fearfulness.

BACKGROUND: Animal studies have shown that prenatal stress has persisting effects on several aspects of offspring development; more recent studies show that this effect may be eliminated by positive postnatal rearing. Human studies of prenatal anxiety/stress are now also beginning to document links between antenatal stress/anxiety and behavioural and cognitive development of the child; however, there is no human evidence as to whether the early caregiving environment moderates the effect of antenatal anxiety/stress on child outcomes. METHODS: Antenatal and postnatal measures of stress were collected on 123 women who were recruited from an antenatal clinic. Laboratory-based assessment of the children's cognitive development and fearfulness were assessed when the children were aged 17 months. In addition, child-parent attachment quality was assessed using the Strange Situation. RESULTS: Attachment classification moderated the link between antenatal stress and observed fearfulness. The effect of antenatal stress on fearfulness was most accentuated in children with an Insecure/Resistant attachment classification; the significant antenatal stress x attachment classification interaction held after controlling for postnatal stress and obstetric, social and demographic factors. Attachment did not moderate the effects of antenatal anxiety on cognitive development. DISCUSSION: These findings provide the first human evidence that postnatal parenting may moderate the adverse effects of antenatal stress. These results raise developmental questions about the timing and effect of interventions to reduce the adverse effects of antenatal stress exposure.

Postnatal depression and mother and infant outcomes after infant massage.

BACKGROUND: Postnatal depression can be a long lasting condition which affects both the mother and her baby. A pilot study indicated that attending baby massage improved maternal depression and mother-infant interactions. The current study further investigates any benefits of baby massage for mothers with postnatal depression and their infants. METHODS: Mothers scoring (3)13 on the Edinburgh Postnatal Depression Scale (EPDS) at 4 weeks postpartum were randomly assigned to attend baby massage classes (n=31) or a support group (n=31). They completed depression, anxiety and Infant Characteristics Questionnaires and were filmed interacting with their infants before and after 6 intervention sessions, and at one year. Thirty four non-depressed mothers also completed the study. RESULTS: More of the massage than support group mothers showed a clinical reduction in EPDS scores between four weeks and outcome (p<0.05). At one year, massage-group mothers had non-depressed levels of sensitivity of interaction with their babies, whereas the support group did not. There were no other differences in either mother or child between the two intervention groups. Depressed mothers did not achieve control depression or anxiety scores at one year. LIMITATIONS: For ethical reasons, the study did not include a control group of depressed mothers who did not receive an intervention. CONCLUSIONS: Both intervention groups showed reductions in depression scores across the study period, but the massage group did better on some indices. They also had somewhat better interactions with their infants at one year, but these effects were limited.

Associations between maternal prenatal cortisol and fetal growth are specific to infant sex: findings from the Wirral Child Health and Development Study.

Recent findings highlight that there are prenatal risks for affective disorders that are mediated by glucocorticoid mechanisms, and may be specific to females. There is also evidence of sex differences in prenatal programming mechanisms and developmental psychopathology, whereby effects are in opposite directions in males and females. As birth weight is a risk for affective disorders, we sought to investigate whether maternal prenatal cortisol may have sex-specific effects on fetal growth. Participants were 241 mothers selected from the Wirral Child Health and Development Study (WCHADS) cohort (n=1233) using a psychosocial risk stratifier, so that responses could be weighted back to the general population. Mothers provided saliva samples, which were assayed for cortisol, at home over 2 days at 32 weeks gestation (on waking, 30-min post-waking and during the evening). Measures of infant birth weight (corrected for gestational age) were taken from hospital records. General population estimates of associations between variables were obtained using inverse probability weights. Maternal log of the area under the curve cortisol predicted infant birth weight in a sex-dependent manner (interaction term P=0.029). There was a positive and statistically significant association between prenatal cortisol in males, and a negative association in females that was not statistically significant. A sex interaction in the same direction was evident when using the waking (P=0.015), and 30-min post-waking (P=0.013) cortisol, but not the evening measure. There was no interaction between prenatal cortisol and sex to predict gestational age. Our findings add to an emerging literature that suggests that there may be sex-specific mechanisms that underpin fetal programming.

Endogenous oxidized indoles share inhibitory potency against [3H]isatin binding in rat brain.

Isatin is an endogenous oxidized indole that influences a range of processes in vivo and in vitro. It has a distinct and discontinuous distribution in the brain and [3H]isatin binding sites are widely distributed in rat brain sections. The highest labelling is found in hypothalamic nuclei and in the cortex, hippocampus, and cerebellum (Crumeyrolle-Arias et al., 2003). However, the properties of most isatin binding sites and their physiological ligands remain unknown. In the present study the effects of three endogenous oxidized indoles (oxindole, 5-hyxdoxyoxindole, and isatin) on [3H]isatin binding were investigated in rat brain sections. In most regions cold isatin (0.2 mM) significantly reduced [3H]isatin binding. In addition to isatin, the other endogenous oxidized indoles, 5-hydroxyoxindole and oxindole were effective in displacing [3H]isatin. Total irreversible inhibition of monoamine oxidases caused inhibition of specific [3H]isatin binding in 7 of 10 brain region studied. This was accompanied by altered sensitivity of [3H]isatin binding to these indoles, including regions where a decrease of specific binding was not detected. The combinations of the three oxidized indoles produced two clear effects: augmentation (potentiation) and attenuation (blockade) of inhibitory activity compared with the independent effects of these compounds. The different effects of oxidized indoles and their combinations (isatin + 5-hydroxyoxindole and isatin + oxindole) in various brain regions therefore suggest an interaction of [(3H]isatin with different and multiple isatin-binding sites, which exhibit different sensitivity to endogenous oxidizing indoles.

Isatin interaction with glyceraldehyde-3-phosphate dehydrogenase, a putative target of neuroprotective drugs: partial agonism with deprenyl.

There is evidence that the binding of deprenyl, a monoamine oxidase (MAO) B inhibitor, and other propargylamines to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is primarily responsible for their neuroprotective and antiapoptotic effects. Thus, GAPDH may be a target for other neuroprotective drugs. Using two independent approaches, radioligand analysis and an optical biosensor technique, we demonstrate here that GAPDH also interacts with the endogenous, reversible MAO B inhibitor, isatin. Deprenyl inhibited both [3H]isatin binding to GAPDH, and the binding of this enzyme to an isatin analogue, 5-aminoisatin, immobilized on to an optical biosensor cell. Another MAO inhibitor, tranylcypromine, was ineffective. Both deprenyl and isatin inhibited GAPDH-mediated cleavage of E. coli tRNA, and their effects were not additive. We suggest that isatin may be an endogenous partial functional agonist of deprenyl in its effect on GAPDH and GAPDH-mediated RNA cleavage. Changes in level of endogenous isatin may influence the neuroprotective effect of deprenyl in vivo.

A Role for the Placenta in Programming Maternal Mood and Childhood Behavioural Disorders.

Substantial data demonstrate that the early-life environment, including in utero, plays a key role in later life disease. In particular, maternal stress during pregnancy has been linked to adverse behavioural and emotional outcomes in children. Data from human cohort studies and experimental animal models suggest that modulation of the developing epigenome in the foetus by maternal stress may contribute to the foetal programming of disease. Here, we summarise insights gained from recent studies that may advance our understanding of the role of the placenta in mediating the association between maternal mood disorders and offspring outcomes. First, the placenta provides a record of exposures during pregnancy, as indicated by changes in the placental trancriptome and epigenome. Second, prenatal maternal mood may alter placental function to adversely impact foetal and child development. Finally, we discuss the less well established but interesting possibility that altered placental function, more specifically changes in placental hormones, may adversely affect maternal mood and later maternal behaviour, which can also have consequence for offspring well-being.

Isatin, an endogenous monoamine oxidase inhibitor, triggers a dose- and time-dependent switch from apoptosis to necrosis in human neuroblastoma cells.

Isatin is an endogenous indole that is increased in stress, inhibits monoamine oxidase (MAO) B and improves bradykinesia and striatal dopamine levels in rat models of Parkinson's disease. Consequently, it has been suggested that isatin might be a possible treatment for Parkinson's disease although little is known about its effects on neural cell growth and survival. The aim of this study was to investigate the survival of dopaminergic human neuroblastoma (SH-SY5Y) cells following treatment with increasing concentrations of isatin. SH-SY5Y cells were exposed to isatin for defined time points, after which cell survival was determined by MTT assay. A combination of Annexin V binding and propidium iodide (PI) exclusion was used to distinguish apoptosis from necrosis in flow cytometry experiments and FACS profiles of permeabilised PI-labelled cells were employed for the assessment of cell cycle distribution. Isatin treatment (1-400 microM) for 24h induced a significant dose-dependent increase in MTT metabolism by SH-SY5Y cells in culture, but this was not due to an increase in cell division. At the higher concentrations (200-400 microm) isatin triggered cell death, although MTT metabolism was still increased in the culture, suggesting that surviving cells were hypermetabolic. Following a longer (48 h) exposure, isatin was found to cause cell death in a dose-dependent manner; at lower concentrations (50 microM), the predominant mode of cell death was apoptosis while at the highest concentration (400 microm) increasing numbers of necrotic cells were also evident. Thus, in dopaminergic SH-SY5Y cells isatin induces cell death in dose- and time-dependent manner. This death occurred as a continuum of survival, apoptosis and necrosis. Our results re-emphasise that caution should be exercised when considering high doses of isatin as a putative anti-Parkinson's disease therapeutic.

Brain monoamine oxidase activity in schizophrenics and controls.

Postmortem samples of caudate nucleus and frontal cortex from schizophrenic, schizophrenic-like, and control subjects were examined for monoamine oxidase activity using dopamine, phenylethylamine, and 5-hydroxytryptamine as substrates. There were no significant differences between the diagnostic groups with any of the three substrates. Neither was there a difference between the sexes, nor a consistent relationship of enzyme activity to age.

Fetal plasma testosterone correlates positively with cortisol.

BACKGROUND: Fetal exposure to testosterone has been implicated in programming childhood behaviour, but little is known about the determinants of fetal testosterone concentrations. AIMS: To investigate the relation between fetal testosterone and maternal and fetal cortisol. METHODS: Clinically indicated blood samples taken from 44 human fetuses (mean gestational age 27 weeks, range 15-38), together with paired maternal samples, were analysed for testosterone and cortisol concentrations. RESULTS: Male fetuses had significantly higher concentrations of testosterone than females. Female but not male fetal concentrations rose significantly with gestational age. Fetal testosterone correlated positively with both fetal cortisol and maternal testosterone concentrations. Multiple regression showed that maternal testosterone and fetal cortisol were independently correlated with fetal plasma testosterone in both sexes. CONCLUSION: Unlike the norm in the adult, where testosterone production is often inhibited by cortisol, in the fetus there is a positive link between the two.

The effects of acute relaxation on indices of anxiety during pregnancy.

OBJECTIVES: Antenatal maternal anxiety has adverse effects on the fetus and the child. In this study we determined whether a short period of directed or of passive relaxation reduced maternal self-rated anxiety, heart rate, plasma catecholamines, cortisol and uterine artery resistance index, in pregnant women. METHODS: Fifty-eight women (28-32 wks gestation) were assigned randomly to a session of directed active or passive (sitting quietly) relaxation. Spielberger self-rating anxiety questionnaires were completed, and a venous blood sample taken, before and after a Doppler scan. RESULTS: Both active and passive relaxation significantly reduced State Anxiety and maternal heart rate, but the effect was significantly greater with the active relaxation. In contrast, the passive relaxation significantly reduced noradrenaline levels whereas active did not. Adrenaline levels were not changed significantly with either type of relaxation. Both methods significantly reduced cortisol, with a trend for the passive to have a greater effect. The active relaxation had no effect on uterine artery blood flow, whereas there was a statistically significant, but clinically negligible, increase in mean resistance index after passive relaxation. CONCLUSION: Both methods reduced maternal State Anxiety and heart rate, the active method more so. However there was a striking lack of correlation with the other biological indices studied. In order to reduce specific biological effects of anxiety during pregnancy, different methods may be needed from those which are most effective at reducing subjective anxiety.

Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses.

Paired fetal and maternal samples were obtained, at fetal blood sampling and intrauterine transfusion, to study hypothalamic-pituitary-adrenal stress responses. This confirmed that the fetus mounts an hypothalamic-pituitary-adrenal stress response to transfusion via the intrahepatic vein, which involves piercing the fetal trunk, but not to transfusion via the placental cord insertion [mean cortisol response via intrahepatic vein delta = 52.6 nmol/L, 95% CI (25.3-79.9), P = 0.001; mean beta-endorphin response delta =106 pg/mL, 95% CI (45.3-167), P = 0.002]. Baseline maternal fetal ratios were 13 [95% CI (10.7-15.2)] for cortisol and 0.8 [95% CI (0.5-1.0)] for beta-endorphin. The novel findings were: 1) that the fetal responses were independent of those of the mother, which did not change during transfusion at either site; 2) that there was a correlation between baseline fetal and maternal cortisol levels (r = 0.58, n = 51, P < 0.0001) but not between baseline fetal and maternal ss-endorphin levels, suggesting cortisol transfer across the placenta, rather than joint control by placental CRH; and 3) that fetal beta-endorphin responses were apparent from 18 weeks gestation and independent of gestational age, whereas fetal cortisol responses were apparent from 20 weeks gestation and were dependent on gestational age (y = -91.4 + 5.08x, r = 0.51; n = 16; P = 0.04; CI for slope, 0.16-10.0), consistent with the maturation of the fetal pituitary before the fetal adrenal.

Raised endogenous monoamine oxidase inhibitor output in postwithdrawal alcoholics: effects of L-dopa and ethanol.

Urinary output of endogenous monoamine oxidase inhibitor was significantly greater in a group of postwithdrawal alcoholics than in controls. An oral dose of 0.5 g of L-dopa reduced output to control values in the alcoholics, but in the controls themselves output was unaffected. A similar excretion pattern to unextracted samples was observed in ethyl acetate extracts of these urine samples, acidified to pH 1. In a second group of postwithdrawal alcoholics, where the L-dopa effect was confirmed, ethanol administration brought about a small but not significant reduction in inhibitor output.

Tyramine conjugation deficit in migraine, tension-type headache, and depression.

This study was designed to investigate tyramine sulfate conjugation in patients with migraine or tension-type headache, as defined by the newly introduced International Headache Society (IHS) criteria and to examine whether this relationship is mediated by major depression. A total of 62 subjects completed the study: 38 with migraine (22 with aura and 16 without aura), 12 with tension-type headache, and 12 controls. Patients with migraine had significantly lower urinary tyramine sulfate excretion following oral tyramine challenge than normal control. Tension-type headache was also associated with low tyramine conjugation, but only when comorbid with depression. Although mean tyramine sulfate output was lower among subjects with major depression within each of the subtypes of headache, no significant main effect emerged for depression or major subtype thereof. The lower tyramine sulfate excretion values among patients with both migraine and depression compared to those of migraine alone or depression alone in our data and those of others suggests that comorbid migraine with depression may represent a more severe form of migraine than migraine alone. The findings underscore the importance of comorbidity in clinical and epidemiological studies of migraine.