Veerle Bergink

Validation of the Edinburgh Depression Scale during pregnancy

BACKGROUND Untreated depression during pregnancy may have adverse outcomes for the mother and her child. Screening for depression in the general pregnant population is thus recommended. The Edinburgh Depression Scale (EDS) is widely used for postpartum depression screening. There is no consensus on which EDS cutoff values to use during pregnancy. The aim of the current study was to examine the predictive validity and concurrent validity of the EDS for all three trimesters of pregnancy. METHODS In a large unselected sample of 845 pregnant women, the sensitivity, specificity, and validity of the EDS were evaluated. The Composite International Diagnostic Interview (depression module) was used to examine the predictive validity of the EDS. The anxiety and somatization subscales of the Symptom Checklist 90 (SCL-90) were used to examine its concurrent validity. Only women with a major depressive episode were considered as cases. RESULTS The prevalence of depression decreased toward end term: 5.6%, 5.4%, and 3.4%. The EDS scores also decreased toward end term, while the SCL-90 subscale anxiety scores increased. The EDS showed high test-retest reliability and high concurrent validity with the SCL-90 anxiety and somatization subscales. The area under the receiver operating characteristic curve was high and varied between 0.93 and 0.97. A cutoff value of 11 in the first trimester and that of 10 in the second and third trimesters gave the most adequate combination of sensitivity, specificity, and positive predictive value. CONCLUSIONS The EDS is a reliable instrument for screening depression during pregnancy. A lower cutoff than commonly applied in the postpartum period is recommended.

Autoimmunity, inflammation, and psychosis: a search for peripheral markers.

Accumulating evidence supports the view that deregulation of the immune system represents an important vulnerability factor for psychosis. In a subgroup of psychotic patients, the high comorbidity with autoimmune and chronic inflammatory conditions suggests a common underlying immune abnormality leading to both conditions. The reviewed data of affective and nonaffective psychosis show that if immune biomarkers exist for such immune abnormality, they may be found in raised macrophage/monocyte inflammatory activation patterns (monocytosis, high-inflammatory gene expression, raised glucocorticoid receptor β/glucocorticoid receptor α ratio, and high levels of proinflammatory and anti-inflammatory monocyte/macrophage derived cytokines in serum/plasma), reduced T cell numbers/proliferation, and TH1 skewing. This activation of the inflammatory response system may be suggestive for microglia activation, as these cells are the macrophages of the brain. Indeed, there is some evidence of activation of the microglia as detected in positron emission tomography scans and in histopathology, and it is assumed that this activation disturbs the development and function of neuronal circuits in the brain. Further, animal models of psychotic conditions (maternal stress and inflammation paradigms) suggest that such monocyte/microglia activation could be seen as the result of a combination of genetic predisposition and an immune-mediated two-hit model. Infection but also environmental stressors during gestation/early life activate microglia, perturbing neuronal development, thereby setting the stage for vulnerability for later psychotic disorders. A second hit, such as endocrine changes, stress, or infection, could further activate microglia, leading to functional abnormalities of the neuronal circuitry in the brain and psychosis.

Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and Meta-Analysis

OBJECTIVE Women with a history of bipolar disorder, postpartum psychosis, or both are at high risk for postpartum relapse. The aim of this meta-analysis was to estimate the risk of postpartum relapse in these three patient groups. METHOD A systematic literature search was conducted in all public medical electronic databases, adhering to the PRISMA guidelines. Studies were included if they reported postpartum relapse in patients diagnosed with bipolar disorder and/or a history of postpartum psychosis or mania according to DSM or ICD criteria or the Research Diagnostic Criteria. RESULTS Thirty-seven articles describing 5,700 deliveries in 4,023 patients were included in the quantitative analyses. The overall postpartum relapse risk was 35% (95% CI=29, 41). Patients with bipolar disorder were significantly less likely to experience severe episodes postpartum (17%, 95% CI=13, 21) than patients with a history of postpartum psychosis (29%, 95% CI=20, 41). Insufficient information was available to determine relapse rates for patients with bipolar disorder and a history of postpartum episodes. In women with bipolar disorder, postpartum relapse rates were significantly higher among those who were medication free during pregnancy (66%, 95% CI=57, 75) than those who used prophylactic medication (23%, 95% CI=14, 37). CONCLUSIONS One-third of women at high risk experience a postpartum relapse. In women with bipolar disorder, continuation of prophylactic medication during pregnancy appears highly protective for maintaining mood stability postpartum. In women with a history of isolated postpartum psychosis, initiation of prophylaxis immediately after delivery offers the opportunity to minimize the risk of relapse while avoiding in utero medication exposure.

Perceived and observed mother-child interaction at time of hospitalization and release in postpartum depression and psychosis

SummaryIntroduction: A pilot study was conducted which compared perceived mother–infant bonding in women admitted with postpartum depression or psychosis, with observations of mother–infant interaction by the nursing staff at both the time of hospitalization and that of release.Method: 25 mother–infant pairs admitted to a psychiatric unit were included in this study. The Postpartum Bonding Questionnaire was used to assess the perceived mother–infant bond and the observation of mother–infant interaction was assessed with the Bethlem Mother–Infant Interaction Scale.Results: At the time of both hospitalization and release postpartum depressed women experienced the bond with their child significantly more negative than women with postpartum psychosis. In contrast to women with postpartum psychosis, the experience of postpartum depressed women was significantly correlated with the observations of the nursing staff at time of release.Conclusion: Treatment that focuses on a mother’s experience of the bond with her child could be especially beneficial for mothers with postpartum depression.

Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder

In this study, we used new technology to investigate whether a coherent pattern of enhanced expression of inflammatory and other immune activation genes in circulating monocytes is found in patients with major depression. Since a high inflammatory state of monocytes might be related to glucocorticoid resistance, we also included the genes for the two isoforms of the glucocorticoid receptor. For this study, we aimed at finding a similar coherent pattern of inflammatory and immune activation genes in monocytes of patients with MDD and recruited 47 medication-free melancholic MDD inpatients and 42 healthy controls. A quantitative-polymerase chain reaction (Q-PCR) monocyte gene expression analysis was performed using a panel of inflammatory-related genes previously identified as abnormally regulated in mood disorder patients. Selected serum cytokines/chemokines were assessed using a cytometric bead array. Depressive symptoms were analysed using Hamilton depression scores (HAMD). Thirty-four of the 47 monocyte inflammatory-related genes were significantly upregulated and 2 were significantly downregulated as compared to controls, the latter including the gene for the active GRα in particular in those with a high HAMD score. The reduced GRα expression correlated strongly to the upregulation of the inflammatory genes in monocytes. Serum levels of IL6, IL8, CCL2 and VEGF were significantly increased in patients compared to controls. Our data show the deregulation of two interrelated homoeostatic systems, that is, the immune system and the glucocorticoid system, co-occurring in major depression.

Immune system dysregulation in first-onset postpartum psychosis

BACKGROUND Accumulating evidence suggests that dysregulation of the immune system represents an important vulnerability factor for mood disorders. Postpartum psychosis (PP) is a severe mood disorder occurring within 4 weeks after delivery, a period of heightened immune responsiveness and an altered endocrine set point. Therefore, the aim of this study was to examine immune activation in patients with first-onset PP at the level of monocytes, T cells, and serum cytokines/chemokines. METHODS We included 63 women admitted with first-onset PP. Control groups included healthy postpartum (n = 56) and nonpostpartum (n = 136) women. A quantitative-polymerase chain reaction monocyte gene expression analysis was performed with 43 genes previously identified as abnormally regulated in nonpostpartum mood disorder patients including the isoforms of the glucocorticoid receptor. Peripheral blood mononuclear cells percentages were measured by fluorescence-activated cell sorter analysis, whereas serum cytokines/chemokines were determined with a cytometric bead array. RESULTS In healthy women, postpartum T cell levels were significantly elevated compared with nonpostpartum. Patients with PP failed to show the normal postpartum T cell elevation. In contrast, these patients showed a significant elevation of monocyte levels and a significant upregulation of several immune-related monocyte genes compared with control subjects postpartum and nonpostpartum. Furthermore, the glucocorticoid receptor α/β gene expression ratio was decreased in monocytes of PP patients, strongly correlating with their immune activation. CONCLUSIONS This study demonstrates a robust dysregulation of the immuno-neuro-endocrine set point in PP, with a notable over-activation of the monocyte/macrophage arm of the immune system.

Heterogeneity of postpartum depression: a latent class analysis

BACKGROUND Maternal depression in the postpartum period confers substantial morbidity and mortality, but the definition of postpartum depression remains controversial. We investigated the heterogeneity of symptoms with the aim of identifying clinical subtypes of postpartum depression. METHODS Data were aggregated from the international perinatal psychiatry consortium Postpartum Depression: Action Towards Causes and Treatment, which represents 19 institutions in seven countries. 17,912 unique subject records with phenotypic data were submitted. We applied latent class analyses in a two-tiered approach to assess the validity of empirically defined subtypes of postpartum depression. Tier one assessed heterogeneity in women with complete data on the Edinburgh postnatal depression scale (EPDS) and tier two in those with postpartum depression case status. FINDINGS 6556 individuals were assessed in tier one and 4245 in tier two. A final model with three latent classes was optimum for both tiers. The most striking characteristics associated with postpartum depression were severity, timing of onset, comorbid anxiety, and suicidal ideation. Women in class 1 had the least severe symptoms (mean EPDS score 10·5), followed by those in class 2 (mean EPDS score 14·8) and those in class 3 (mean EPDS score 20·1). The most severe symptoms of postpartum depression were significantly associated with poor mood (mean EPDS score 20·1), increased anxiety, onset of symptoms during pregnancy, obstetric complications, and suicidal ideation. In class 2, most women (62%) reported symptom onset within 4 weeks postpartum and had more pregnancy complications than in other two classes (69% vs 67% in class 1 and 29% in class 3). INTERPRETATION PPD seems to have several distinct phenotypes. Further assessment of PPD heterogeneity to identify more precise phenotypes will be important for future biological and genetic investigations. FUNDING Sources of funding are listed at the end of the article.

Autoimmune Encephalitis in Postpartum Psychosis

OBJECTIVE Significant immunological alterations have been observed in women with first-onset affective psychosis during the postpartum period. Recent studies have highlighted the possibility that a subset of patients with first-onset severe psychiatric episodes might suffer from undiagnosed autoimmune encephalitis. Therefore, the authors performed a three-step immunohistochemistry-based screening for CNS autoantibodies in a large cohort of patients with postpartum psychosis and matched postpartum comparison subjects. METHOD Ninety-six consecutive patients with postpartum psychosis and 64 healthy postpartum women were included. Screening for antibodies in patient serum was performed using immunohistochemistry. Samples showing any staining were further examined by immunocytochemistry using live hippocampal neurons and cell-based assays to test for anti-N-methyl-d-aspartate (NMDA) receptor antibodies. Cell-based assays for all other known CNS antigens were performed in those samples with immunocytochemistry labeling but negative for NMDA receptor antibodies. RESULTS Four patients (4%) with neuropil labeling suggestive for extracellular antigen reactivity were identified. Serum samples from all four patients showed clear extracellular labeling of live hippocampal neurons. Two women had the specific staining pattern characteristic for anti-NMDA receptor antibody positivity, which was confirmed by cell-based assays. Neither patient with anti-NMDA receptor antibody positivity had evidence of an ovarian teratoma. The other two patients tested negative by cell-based assays for all known CNS antigens. None of the matched postpartum comparison subjects had confirmed neuronal surface antibodies. The two patients with anti-NMDA receptor antibodies both showed extrapyramidal symptoms following initiation of treatment with low-dose haloperidol. CONCLUSIONS In patients with acute psychosis during the postpartum period, systematic screening for anti-NMDA receptor autoantibodies should be considered. The acute onset of severe atypical psychiatric symptoms in young female patients should raise the index of suspicion for anti-NMDA receptor encephalitis, particularly in the setting of neurological symptoms, including extrapyramidal side effects of antipsychotic treatment.

Down-regulation of inflammation-protective microRNAs 146a and 212 in monocytes of patients with postpartum psychosis

BACKGROUND Postpartum psychosis (PP) is thought to belong to the bipolar spectrum. Recently we described an immune activation signature in monocytes of patients with PP using gene expression profiling. Immune activation genes are regulated by microRNAs (miRNAs). We therefore profiled miRNA expression in monocytes of PP patients to identify differentially expressed miRNAs between PP and the healthy state. METHODS In a profiling study we carried out miRNA profiling using TaqMan array human microRNA A cards v2.0 and monocytes of 8 PP patients. Data were analyzed against monocytes of healthy postpartum women (CP). Nine miRNAs were selected and tested using individual Q-PCR in a larger validation study on monocytes of 20 PP patients, 20 CP and 20 healthy non-postpartum women (HC). RESULTS In the validation study miR-146a expression was significantly down-regulated in the monocytes of first onset PP patients as compared to CP and HC; miR-212 expression was significantly down-regulated in PP patients with prior bipolar disorder. In silico miR-146a targeted 4 genes of the previously described monocyte activation signature in bipolar disorder; miR-212 targeted 2 of such genes. In a correlation study decreased expression of miR-146a in monocytes was related to decreased natural T regulator cells in PP patients; decreased miR-212 was correlated to increased Adrenomedulin and decreased IL-6 expression in monocytes and to higher Th2 cell levels. CONCLUSIONS This study identified changes in miR-146a and -212 expression in PP. Since these miRNAs are linked to inflammation, the study strengthens the view that PP is an inflammation-like condition.

All-Cause Mortality in Women With Severe Postpartum Psychiatric Disorders

OBJECTIVE The postpartum period is associated with a high risk of psychiatric episodes. The authors studied mortality in women with first-onset severe psychiatric disorders following childbirth and compared their mortality rates with those in women from the background population including other female psychiatric patients (mothers and childless women). METHOD In a register-based cohort study with linked information from Danish population registers, the authors identified women with first psychiatric inpatient or outpatient contacts 0-3 months postpartum. The main outcome measure was mortality rate ratios (MRRs): deaths from natural causes (diseases and medical conditions) or unnatural causes (suicides, accidents, and homicides). The cohort included 1,545,857 women representing 68,473,423 person-years at risk. RESULTS In total, 2,699 women had first-onset psychiatric disorders 0-3 months postpartum, and 96 of these died during follow-up. Women with postpartum psychiatric disorders had a higher MRR (3.74; 95% CI=3.06-4.57) than non-postpartum-onset mothers (MRR=2.73; 95% CI=2.67-2.79) when compared with mothers with no psychiatric history. However, childless women with psychiatric diagnoses had the highest MRR (6.15; 95% CI=5.94-6.38). Unnatural cause of death represented 40.6% of fatalities among women with postpartum psychiatric disorders, and within the first year after diagnosis, suicide risk was drastically increased (MRR=289.42; 95% CI=144.02-581.62) when compared with mothers with no psychiatric history. CONCLUSIONS Women with severe postpartum psychiatric disorders had increased MRRs compared with mothers without psychiatric diagnoses, and the first year after diagnosis represents a time of particularly high relative risk for suicide in this vulnerable group.