Bennard Doornbos

Supplementation of a low dose of DHA or DHA+AA does not prevent peripartum depressive symptoms in a small population based sample.

BACKGROUND The decrease of maternal docosahexaenoic (DHA) status during pregnancy has been associated with postpartum depression, especially in women with a low intake of DHA. Since the DHA intake in the Netherlands is low, we investigated whether supplementation of low doses of DHA or DHA plus arachidonic acid (AA) during pregnancy and lactation could prevent depressive symptoms and sleep disturbances in this period. METHODS Women were supplemented daily with placebo, DHA (220 mg) or DHA+AA (220 mg each) from week 16 of pregnancy till three months postpartum. Fatty acid analyses were performed in the available plasma samples at 16 and 36 weeks of pregnancy. Depressive symptoms were measured in weeks 16 and 36 of pregnancy and six weeks postpartum using EPDS and within one week postpartum using a blues questionnaire. RESULTS 119 women completed the study. The average frequency of fish intake was low, 0.94 times per week, and did not differ between the groups. The supplementation groups did not differ in mean EPDS scores or changes in EPDS scores, nor in incidence or severity of postpartum blues. Red blood cell DHA, AA and DHA/AA ratio did not correlate with EPDS or blues scores. Indices of sleep quality did not differ between the groups. CONCLUSION Supplementation of 220 mg/day DHA or DHA+AA (220 mg/day each) does not prevent peri-partum depressive symptoms, in a population based sample with low background DHA intake. TRIAL REGISTRATION ISRCTN Register nr. ISRCTN58176213.

The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT.

BACKGROUND Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction. METHODS Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed. RESULTS We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT (p=0.019); MAOA (p=0.044) and COMT (p=0.026), and MAOA x COMT (p<0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum. CONCLUSION We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the GxE concept for depression, but they underline the complexity of this concept, as the cumulating effects of these polymorphic genes (i.e. MAOA+COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods.

Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: a critical review of the literature.

This paper aims to provide an overview of the current state of affairs on psychophysiological factors that may explain the link between depression and adverse outcome in coronary artery disease (CAD) patients. Factors discussed include heart rate variability, inflammation, platelet function, hypothalamus-pituitary-adrenal axis activity, serotonin metabolism and polyunsaturated fatty acids. Evidence suggests the involvement of each of these factors in both depression and CAD, together contributing to the prospective association between depression and cardiac outcome. Unfortunately, the involvement of above factors has been evaluated mostly in isolation, despite their functional interrelations and associations with behavioral factors. Moreover, there may be specific relations between individual symptoms of depression and certain psychophysiological mechanisms, rather than with general depression, further complicating the notion of depression as a cardiotoxic factor. The relatively understudied complexity of the relation between depression and CAD may serve as an explanation for the finding that depression treatment does not or barely affect cardiac outcome. Future studies should focus on the network of psychophysiological (and behavioral) factors to elucidate their precise role and timing in depressed cardiac patients.

Human milk arachidonic acid and docosahexaenoic acid contents increase following supplementation during pregnancy and lactation

INTRODUCTION Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for neurodevelopment. Maternal diet influences milk DHA, whereas milk AA seems rather constant. We investigated milk AA, DHA and DHA/AA after supplementation of AA plus DHA, or DHA alone during pregnancy and lactation. SUBJECTS AND METHODS Women were supplemented with AA+DHA (220mg each/day), DHA (220mg/day) or placebo during pregnancy and lactation. Milk samples were collected at 2 (n=86) and 12 weeks (n=69) postpartum. RESULTS Supplementation of AA+DHA elevated milk AA (week 2, 14%; week 12, 23%) and DHA (43% and 52%) as compared to placebo. DHA tended to decrease milk AA and vice versa. Milk AA, DHA and DHA/AA decreased from 2 to 12 weeks postpartum. CONCLUSIONS Milk AA and in particular DHA are sensitive to maternal supplementation. It seems that maternal AA and notably DHA status decline with advancing lactation.

Supplementation of DHA but not DHA with arachidonic acid during pregnancy and lactation influences general movement quality in 12-week-old term infants

DHA and arachidonic acid (AA) are important for neurodevelopment. A traditional neonatal neurological examination and the evaluation of general movement quality are sensitive techniques for assessing neurodevelopment in young infants. Mildly abnormal general movements at 3 months have been associated with a non-optimal current brain condition. We investigated whether supplementation of DHA during pregnancy and lactation influences the infants brain development and whether additional AA modulates this effect. Healthy women were randomly assigned to DHA (220 mg/d, n 42), DHA+AA (220 mg each/d, n 41) or control (n 36), from about week 17 (range 14-20 weeks) of pregnancy until 12 weeks postpartum. The control and the DHA+AA groups had approximately comparable dietary DHA/AA ratios. The standardised neonatal neurological examination was carried out at 2 weeks. General movement quality was assessed at 2 and 12 weeks. Neither DHA alone nor DHA+AA influenced outcomes in the traditional examination. General movement quality of infants in the DHA group was lower than that of infants in the other two groups, especially at 12 weeks: 61 % of the infants in the DHA group showed mildly abnormal general movements compared with 31 % in the control group (P = 0.008) and 34 % in the DHA+AA group (P = 0.015). We conclude that general movement quality at 12 weeks is sensitive to the maternal dietary DHA/AA balance.

Does tryptophan degradation along the kynurenine pathway mediate the association between pro-inflammatory immune activity and depressive symptoms?

BACKGROUND Several studies have suggested that induced tryptophan (TRP) degradation through the kynurenine (KYN) pathway by the enzyme indoleamine 2,3-dioxygenase (IDO) is implicated in the relation between depression and inflammation. We investigated the role of tryptophan degradation in the relationship between inflammatory markers and depressive symptoms in the Netherlands Study of Depression and Anxiety (NESDA) and hypothesized that tryptophan degradation would mediate (part of) this association. METHODS 2812 Participants of NESDA were included in this study including 1042 persons with current major depressive disorder (MDD). Assessments of C-reactive protein (CRP), interleukin (IL)-6, tumor-necrosis factor (TNF)-α, KYN and TRP were obtained from fasting blood samples at the baseline assessment. Tryptophan degradation was estimated by calculating the ratio [KYN/TRP]. Depressive symptoms were measured with the Inventory of Depressive Symptomatology. RESULTS Significant associations between inflammation and depressive symptoms were found for CRP and IL-6, for the total group and the subgroup of patients with current MDD. Adjustment for KYN/TRP did not attenuate these associations. There were no significant indirect effects for CRP on depressive symptoms mediated by KYN/TRP for the whole group (B=-0.032; 95% CI: -0.103 to 0.028) and for the subgroup of patients with current MDD (B=0.059; 95% CI: -0.037 to 0.165). Also IL-6 did not indirectly affect depressive symptoms through KYN/TRP in the total group (B=-0.023; 95% CI: -0.093 to 0.045) and in the MDD subgroup B=0.052; 95% CI: -0.019 to 0.144). Finally, no significant relation between depressive symptoms and KYN/TRP was found in the whole group (β=-0.019, p=0.311) nor in the subgroup with MDD (β=0.025, p=0.424). CONCLUSIONS We did not find indications for tryptophan degradation, measured by KYN/TRP, to mediate the relationship between inflammation and depressive symptoms.

Sequential serotonin and noradrenalin associated processes involved in postpartum blues

OBJECTIVE We investigated whether postpartum blues was related to changes in parameters of noradrenergic and serotonergic functioning. METHODS From 26 healthy pregnant women blood was collected at the end of pregnancy and 5 days and 6 weeks postpartum. Serotonergic parameters were: platelet serotonin content; paroxetine binding to platelet membranes as an index of serotonin transporter activity; the serotonin precursor tryptophan in proportion to the large neutral amino acids, as an estimate of its cerebral influx. Noradrenergic indices were the noradrenaline precursor tyrosine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). The Kennerly and Gath blues questionnaire was applied at day five postpartum. RESULTS The incidence of postpartum blues was 30%. The tryptophan ratio and serotonin content of platelets were decreased (p<0.01) at day five postpartum in all women. Bmax paroxetine at day five was correlated with blues score (beta=0.460; p=0.031). MHPG levels at 6 weeks were increased in women with blues (p<0.001). In a regression model MHPG at 6 weeks was related to blues score (beta=0.477; p=0.002) and MHPG at day five (beta=0.550; p=0.001), explaining >50% of the variation (R2=0.588; p<0.001). CONCLUSIONS A decreased serotonergic activity was found at the fifth day postpartum in all subjects. Increased SERT activity, reflected by higher paroxetine binding to platelets might be involved in the onset of blues. The elevated MHPG levels in women with blues are compatible with a higher stress sensitivity, or a decreased stress coping in those and is suggested to be involved with the onset of depression.

Abrupt rather than gradual hormonal changes induce postpartum blues-like behavior in rats

AIMS Postpartum blues is thought to be related to hormonal events accompanying delivery. We investigated whether blues-like symptoms depend on the rate of the decline of hormones, by comparing the behavioral consequences of an abrupt versus a gradual decline of gonadal hormones in an animal model. METHODS Female rats were treated with estrogen and progesterone for 23 days, administered either by injections or by subcutaneously implanted tubes filled with hormones. A gradual hormone decline was achieved by discontinuation of the injections; and rapid decline by removal of the tubes. Control groups received either a continued treatment or no hormones. In the period following the decline the stress-reactivity was tested with an acoustic startle test on 3 consecutive days, and anxiety behavior with an open-field test on the 2nd day. The Hypothalamus-, Pituitary-, Adrenal-axis (HPA-axis) response to stress was measured by assessing the corticosterone levels and hypothalamic c-fos expression stress-response at the 4th day. KEY FINDINGS The rapid decline of hormones induced an increased startle response lasting for two days, and increased anxiety-like behavior in the open field. This was not found in the gradual-decline and control groups. The HPA-axis response to stress was decreased in all hormone-treated animals. SIGNIFICANCE This animal study suggests that: 1) abrupt rather than gradual hormonal changes induce increased stress-reactivity and anxiety-like behavior; 2) postpartum blues may result from differences in the capacity to adapt to the changes of gonadal hormones; 3) Recovery of pregnancy-induced diminished HPA-axis response is independent of the postpartum hormone kinetics.

Comparing cognitive and somatic symptoms of depression in myocardial infarction patients and depressed patients in primary and mental health care.

Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients.

The association between the hypothalamic pituitary adrenal axis and tryptophan metabolism in persons with recurrent major depressive disorder and healthy controls

OBJECTIVES Persistent changes in serotonergic and hypothalamic pituitary adrenal (HPA) axis functioning are implicated in recurrent types of major depressive disorder (MDD). Systemic tryptophan levels, which influence the rate of serotonin synthesis, are regulated by glucocorticoids produced along the HPA axis. We investigated tryptophan metabolism and its association with HPA axis functioning in single episode MDD, recurrent MDD and non-depressed individuals. METHODS We included depressed individuals (n = 1320) and controls (n = 406) from the Netherlands Study of Depression and Anxiety (NESDA). The kynurenine to tryptophan ratio (kyn/trp ratio) was established using serum kynurenine and tryptophan levels. Several HPA axis parameters were calculated using salivary cortisol samples. We adjusted the regression analyses for a wide range of potential confounders and differentiated between single episode MDD, recurrent MDD and control. RESULTS Tryptophan, kynurenine and the kyn/trp ratio did not differ between controls and depressed individuals. Increased evening cortisol levels were associated with a decreased kyn/trp ratio in the total sample (Crude: β = -.102, p < .001; Adjusted: β = -.083, p < .001). This association was found to be restricted to recurrently depressed individuals (Crude: β = -.196, p < .001; Adjusted: β = -.145, p = .001). Antidepressant treatment did not affect this association. CONCLUSIONS Our results suggest that an imbalance between HPA axis function and tryptophan metabolism could be involved in recurrent depression.