Review of the Assessment and Management of Perinatal Mood and Anxiety Disorders.

Perinatal mood and anxiety disorders (PMADs) are the most common complication of childbirth. When poorly controlled, they are associated with worse obstetric outcomes, such as higher rates of preterm birth and unplanned cesarean delivery. They are also associated with suicide, a leading cause of perinatal maternal death. This article provides an overview of evidence-based recommendations for screening, assessment, and management of PMADs, including suicide risk assessment and management and pharmacological and nonpharmacological treatment options compatible with pregnancy and lactation. Although specialized reproductive psychiatrists can provide expert guidance for the management of PMADs, their scarcity means that most patients will not have access to this expert care and instead will seek guidance from general psychiatrists. This article provides a clinical guide for generalists that is based on the best current evidence, including recently released treatment guidelines.

The immune phenotype of perinatal anxiety in an anxiety-focused behavioral intervention program in Pakistan.

BACKGROUND: Dysregulation of the immune system has been associated with psychiatric disorders and pregnancy-related complications, such as perinatal depression. However, the immune characteristics specific to perinatal anxiety remain poorly understood. In this study, our goal was to examine specific immune characteristics related to prenatal anxiety within the context of a randomized controlled trial designed to alleviate anxiety symptoms-the Happy Mother - Healthy Baby (HMHB) study in Rawalpindi, Pakistan. MATERIALS AND METHODS: Pregnant women (n = 117) were followed prospectively in the 1st, 2nd, and 3rd trimesters (T1, T2, T3) and at 6 weeks postpartum (PP6). Each visit included a blood draw and anxiety evaluation (as measured by the anxiety subscale of the Hospital Anxiety and Depression Scale - HADS -using a cutoff ≥ 8). We enrolled both healthy controls and participants with anxiety alone; those with concurrent depression were excluded. RESULTS: K-means cluster analysis revealed three anxiety clusters: Non-Anxiety, High and Consistent Anxiety, and Decreasing Anxiety. Principal components analysis revealed two distinct clusters of cytokine and chemokine activity. Women within the High and Consistent Anxiety group had significantly elevated chemokine activity across pregnancy (in trimester 1 (ß = 0.364, SE = 0.178, t = 2.040, p = 0.043), in trimester 2 (ß = 0.332, SE = 0.164, t = 2.020, p = 0.045), and trimester 3 (ß = 0.370, SE = 0.179, t = 2.070, p = 0.040) compared to Non-Anxiety group. Elevated chemokine activity was associated with low birthweight (LBW) and small for gestational age (SGA). CONCLUSION: Our findings reveal a unique pattern of immune dysregulation in pregnant women with anxiety in a Pakistani population and offer preliminary evidence that immune dysregulation associated with antenatal anxiety may be associated with birth outcomes. The dysregulation in this population is distinct from that in our other studies, indicating that population-level factors other than anxiety may play a substantial role in the differences found. (Clinicaltrials.gov # NCT04566861).

Dysregulated placental expression of kynurenine pathway enzymes is associated with inflammation and depression in pregnancy.

BACKGROUND: Perinatal depression (including antenatal-, postnatal-, and depression that spans both timepoints) is a prevalent disorder with high morbidity that affects both mother and child. Even though the full biological blueprints of perinatal depression remain incomplete, multiple studies indicate that, at least for antenatal depression, the disorder has an inflammatory component likely linked to a dysregulation of the enzymatic kynurenine pathway. The production of neuroactive metabolites in this pathway, including quinolinic acid (QUIN), is upregulated in the placenta due to the multiple immunological roles of the metabolites during pregnancy. Since neuroactive metabolites produced by the pathway also may affect mood by directly affecting glutamate neurotransmission, we sought to investigate whether the placental expression of kynurenine pathway enzymes controlling QUIN production was associated with both peripheral inflammation and depressive symptoms during pregnancy. METHODS: 68 placentas obtained at birth were analyzed using qPCR to determine the expression of kynurenine pathway enzymes. Cytokines and metabolites were quantified in plasma using high-sensitivity electroluminescence and ultra-performance liquid chromatography, respectively. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) throughout pregnancy and the post-partum. Associations between these factors were assessed using robust linear regression with ranked enzymes. RESULTS: Low placental quinolinate phosphoribosyl transferase (QPRT), the enzyme responsible for degrading QUIN, was associated with higher IL-6 and higher QUIN/kynurenic acid ratios at the 3rd trimester. Moreover, women with severe depressive symptoms in the 3rd trimester had significantly lower placental expression of both QPRT and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD); impaired activity of these two enzymes leads to QUIN accumulation. CONCLUSION: Overall, our data support that a compromised placental environment, featuring low expression of critical kynurenine pathway enzymes is associated with increased levels of plasma cytokines and the dysregulated kynurenine metabolite pattern observed in depressed women during pregnancy.

Blood extracellular vesicles carrying brain-specific mRNAs are potential biomarkers for detecting gene expression changes in the female brain.

The absence of non-invasive tests that can monitor the status of the brain is a major obstacle for psychiatric care. In order to address this need, we assessed the feasibility of using tissue-specific gene expression to determine the origin of extracellular vesicle (EV) mRNAs in peripheral blood. Using the placenta as a model, we discovered that 26 messenger RNAs that are specifically expressed in the placenta are present in EVs circulating in maternal blood. Twenty-three of these transcripts were either exclusively or highly expressed in maternal blood during pregnancy only and not in the postpartum period, verifying the feasibility of using tissue-specific gene expression to infer the tissue of origin for EV mRNAs. Using the same bioinformatic approach, which provides better specificity than isolating L1 cell-adhesion molecule containing EVs, we discovered that 181 mRNAs that are specifically expressed in the female brain are also present in EVs circulating in maternal blood. Gene set enrichment analysis revealed that these transcripts, which are involved in synaptic functions and myelination, are enriched for genes implicated in mood disorders, schizophrenia, and substance use disorders. The EV mRNA levels of 13 of these female brain-specific transcripts are associated with postpartum depression (adjusted p-vals = 3 × 10-5 to 0.08), raising the possibility that they can be used to infer the state of the brain. In order to determine the extent to which EV mRNAs reflect transcription in the brain, we compared mRNAs isolated from cells and EVs in an iPSC-derived brain microphysiological system differentiated for 3 and 9 weeks. We discovered that, although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular RNA expression changes in the brain via EV mRNA levels. Our findings bring EV mRNAs to the forefront of peripheral biomarker development efforts in psychiatric diseases by demonstrating the feasibility of inferring transcriptional changes in the brain via blood EV mRNA levels.

Outcomes at the Motherhood Center: A Comparison of Virtual and On-Site Versions of a Specialized Perinatal Partial Hospitalization Program.

OBJECTIVES: Remotely administered mental health care is becoming increasingly common for treatment of a range of psychiatric disorders; however, there is a dearth of literature overviewing direct comparisons between remote and in-person interventions for treatment of Perinatal Mood and Anxiety Disorders (PMADs). The sudden advent of the Covid-19 pandemic in New York City forced an abrupt conversion for an intensive day treatment program for new mothers with PMADs, from an on-site to a remote program. METHODS: The current report compares outcomes of 81 women who completed the program in-person to those of 60 women who completed the program remotely. RESULTS: Improvement in depression scores was statistically superior in the remote program, and improvement in mother-infant bonding was statistically equivalent between the on-site and remote programs. DISCUSSION: These findings indicate that specialized partial hospitalization treatment for individuals with moderate to severe psychiatric illness can be effectively provided via telehealth, thus offering improved convenience, accessibility, and safety without compromising care. We conclude that remotely administered group psychotherapy is an effective intervention for women with moderate to severe PMADs.

Current pharmacotherapy approaches and novel GABAergic antidepressant development in postpartum depression.

Postpartum depression has deleterious effects on childbearing persons globally. Existing treatments have been largely extrapolated from those for other forms of depression and have included pharmacotherapy, psychotherapy, and neuromodulation. Hormonal treatments with oestrogen and progestogens, thought to be a rational approach to treatment in response to an emerging literature on the pathophysiology of postpartum depression, have only limited evidence for efficacy to date. Novel antidepressant development with allopregnanolone analogues, in contrast, has proven a promising avenue for the development of rationally designed and efficacious treatments. This state-of-the-art review presents the evidence for the current standard-of-care pharmacotherapy, hormonal treatment, and emerging allopregnanolone analogues for the treatment of postpartum depression along with a discussion of the current understanding of its neuroactive steroid-driven pathophysiology.

Vitamin D levels and anxiety symptomatology in pregnancy and the postpartum.

Anxiety and vitamin D deficiency are both common in pregnancy, but research into the relationship between vitamin D levels and perinatal anxiety is sparse. We sought to examine whether an association exists and compare the distribution of vitamin D levels in women with and without anxiety symptoms. We analyzed 25-hydroxyvitamin D using ab213966 25(OH) vitamin D enzyme-linked immunosorbent assay in 54 women with and 47 women without anxiety symptoms at the first, second, and third trimesters and at 6 weeks postpartum. We conducted univariate and chi-square analyses to compare the frequencies of non-optimal and optimal vitamin D levels between the anxiety and non-anxiety groups at each timepoint. Overall, vitamin D levels were lower in the first and second trimesters than in the third trimester. In the first trimester only, the non-anxiety group had a marginally higher proportion of women with optimal vitamin D levels when compared to the anxiety group. Many pregnant women have insufficient or deficient levels of vitamin D, and our exploratory findings point to the need for further research into whether this differs between women with anxiety compared to healthy women.

Metabolites of progesterone in pregnancy: Associations with perinatal anxiety.

BACKGROUND: Anxiety disorders are the most common psychiatric disorder during the perinatal period and one of the major risk factors for postpartum depression, yet we know little about biological factors in the etiology of perinatal anxiety. A growing literature points to neuroactive steroid (NAS) dysregulation in perinatal mental illness, but directionality has not been clearly demonstrated, results are not consistent, and no studies have investigated NAS in a population with pure anxiety without comorbid depression. We aimed to add to the limited literature by examining the association between anxiety without comorbid depression and metabolic pathways of NAS longitudinally across the peripartum. METHODS: We measured anxiety symptoms by psychological scales and NAS levels using Gas Chromatography-Mass Spectrometry (GC-MS) at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in n = 36 women with anxiety and n = 38 healthy controls. The anxiety group was determined by a data-driven approach, and cross-sectional and longitudinal statistical methods were used to examine the relationship between the study population and NAS. RESULTS: We found that anxiety had a significant moderating effect on the relationship between progesterone and allopregnanolone, with no such effect for the relationships between progesterone and the intermediate (5α-DHP) or isomeric (isoallopregnanolone) compounds in this pathway, and no effects on the corresponding pathway converting progesterone to pregnanolone and epipregnanolone. We also found a less precipitous decline in the ratio of allopregnanolone to progesterone between T3 and W6 in the anxiety group compared to the non-anxiety group. A genotype analysis of a single-nucleotide polymorphism in the AKR1C2 gene demonstrated that the relationship of allopregnanolone to the intermediate metabolite, 5α-DHP, differed by genotype. CONCLUSION: Our exploratory findings indicate that, for pregnant people with anxiety, metabolism is shunted more aggressively toward the endpoint of the progesterone to allopregnanolone metabolic pathway than it is for those without anxiety.

Biological Mechanisms in Pregnant Women With Anxiety (Happy Mother-Healthy Baby Supplement Study): Protocol for a Longitudinal Mixed Methods Observational Study.

BACKGROUND: Anxiety and depression are common in the perinatal period and negatively affect the health of the mother and baby. Our group has developed "Happy Mother-Healthy Baby" (HMHB), a cognitive behavioral therapy-based psychosocial intervention to address risk factors specific to anxiety during pregnancy in low- and middle-income countries (LMICs). OBJECTIVE: The purpose of this study is to examine biological mechanisms that may be linked to perinatal anxiety in conjunction with a randomized controlled trial of HMHB in Pakistan. METHODS: We are recruiting 120 pregnant women from the Holy Family Hospital, a public facility in Rawalpindi, Pakistan. Participants are assessed for at least mild anxiety symptoms using the Hospital Anxiety and Depression Scale (ie, a score ≥8 on the anxiety scale is necessary for inclusion in the anxiety groups and <8 for inclusion in the healthy control group). Women who meet the criteria for an anxiety group are randomized into either the HMHB intervention group or an enhanced usual care (EUC) control group. Participants receive HMHB or EUC throughout pregnancy and undergo blood draws at 4 time points (baseline, second trimester, third trimester, and 6 weeks post partum). We will assess peripheral cytokine concentrations using a multiplex assay and hormone concentrations using gas chromatography and mass spectrometry. The statistical analysis will use generalized linear models and mixed effects models to assess the relationships across time among anxiety, immune dysregulation, and hormone levels, and to assess whether these biological factors mediate the relationship between anxiety and birth and child development outcomes. RESULTS: Recruitment started on October 20, 2020, and data collection was completed on August 31, 2022. The start date for recruitment for this biological supplement study was delayed by approximately half a year due to the COVID-19 pandemic. The trial was registered at ClinicalTrials.gov (NCT03880032) on September 22, 2020. The last blood samples were shipped to the United States on September 24, 2022, where they will be processed for analysis. CONCLUSIONS: This study is an important addition to the HMHB randomized controlled trial of an intervention for antenatal anxiety. The intervention itself makes use of nonspecialist providers and, if effective, will represent an important new tool for the treatment of antenatal anxiety in LMICs. Our biological substudy is one of the first attempts to link biological mechanisms to antenatal anxiety in an LMIC in the context of a psychosocial intervention, and our findings have the potential to significantly advance our knowledge of the biological pathways of perinatal mental illness and treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03880032; https://clinicaltrials.gov/ct2/show/NCT03880032. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43193.

Anxiety in pregnancy and stress responsiveness: An exploratory study of heart rate variability, cortisol, and alpha-amylase in the third trimester.

The present study aimed to explore the association between anxiety symptoms, including sleep, and physiological stress responsiveness in pregnant women with and without anxiety, as identified by psychiatric diagnosis. Fifty-four pregnant women with (n = 25) and without (n = 29) anxiety completed a laboratory cognitive stressor (the Stroop Color-Word Task) during the third trimester. Heart rate variability (HRV) (as the root mean square of successive differences, RMSSD) was recorded during baseline, stressor, and recovery periods. Salivary cortisol (sCORT) and alpha amylase (sAA) were measured at four timepoints surrounding the stressor task. Psychometric scales (Penn State Worry Questionnaire [PSWQ], Perceived Stress Scale [PSS], Spielberg Trait Anxiety Inventory Scale [STAI], and Pittsburgh Sleep Quality Index [PSQI]) were collected. Women in the anxiety group exhibited significantly less rebound in HRV (RMSSD, change of 4-ms difference, p = .025) from baseline to recovery following the Stroop than did those in the non-anxiety group. Neither neuroendocrine measure (sCORT, sAA) differed between groups at any measurement period. Across the recording period, lower reported sleep quality (PSQI, p = .0092) and higher subjective stress (PSS, p = .039) were associated with lower RMSSD. The findings suggest that women with and without anxiety in late pregnancy display differences in the degree of autonomic rebound as indicated by HRV following a stressor. In addition, levels of HRV over time were associated with subjective perceptions of increased stress and poor sleep. PREGNANCY AND ANXIOUS: The Role of the Immune and Endocrine Systems (NCT03664128).

Setting Common Standards for Reproductive Psychiatry Education: Effectiveness of the National Curriculum in Reproductive Psychiatry.

OBJECTIVE: The National Curriculum in Reproductive Psychiatry (NCRP) provides standardized education for psychiatry residency training programs. The authors hypothesized that residents' preparedness to treat reproductive psychiatric concerns and their medical knowledge would improve following teaching with the NCRP. METHODS: Pre- and post-assessments were administered to residents enrolled in two waves of pilot NCRP training (Early-Modules and All-Modules). Data were collected by individual survey, and pre- and post-responses matched via anonymous ID. Statistical analyses were conducted using R version 3.5.3 and included paired Student's t-tests and a chi-square test. RESULTS: Thirty-eight residents completed the Early-Modules survey and 16 the All-Modules survey. In both groups, there was significant improvement in preparedness to treat pregnant and postpartum women with mental illness (p<0.05). Scores on the 29-point knowledge test rose by 2.5 points in the Early-Modules group and 4.3 points in the All-Modules group (p<0.001 for both). In both cohorts, a majority of residents felt reproductive psychiatry was among the top three specialties needed to become competent independent adult psychiatrists. CONCLUSIONS: Classroom training with local faculty using a standardized curriculum is feasible and results in substantial and significant improvements in both feelings of preparedness and medical knowledge. Psychiatry trainees view training in reproductive psychiatry as an important and missing aspect of their education. Dissemination of a standardized curriculum may help to forge a path toward subspecialty certification for reproductive psychiatry, and can be used as a model for other specialties.

Altered extracellular mRNA communication in postpartum depression is associated with decreased autophagy.

We investigated whether extracellular RNA communication, which is a recently discovered mode of intercellular communication that is involved in a variety of important biological processes including pregnancy, is associated with postpartum depression (PPD). Extracellular RNA communication is increased during pregnancy and is involved in embryo implantation, uterine spiral artery remodeling, parturition, preterm birth, immunity, and the inflammatory response. Since immune anomalies are associated with PPD, we characterized the mRNA content of extracellular vesicles (EV) in a cohort of prospectively collected blood plasma samples at six time-points throughout pregnancy and the postpartum (2nd trimester, 3rd trimester, 2 weeks postpartum, 6 weeks postpartum, 3 months postpartum, and 6 months postpartum) in an academic medical setting from women who went on to develop PPD (N = 7, defined as euthymic in pregnancy with postpartum-onset depressive symptoms assessed by Edinburgh Postnatal Depression Scale ≥13 at any postpartum time point) and matched unaffected controls (N = 7, defined as euthymic throughout pregnancy and postpartum). Blood samples were available for all participants at the T2 and W6 timepoints, with fewer samples available at other time points. This analysis revealed that EV mRNA levels during pregnancy and the postpartum period were extensively altered in women who went on to develop PPD. Gene set enrichment analysis revealed that mRNAs associated with autophagy were decreased in PPD cases. In contrast, EV mRNAs from ribosomes and mitochondria, two organelles that are selectively targeted by autophagy, were elevated in PPD cases. Cellular deconvolution analysis discovered that EV mRNAs associated with PPD originated from monocytes and macrophages. Quantitative PCR analysis for four relevant genes in another cohort replicated these findings and confirmed that extracellular RNA levels are altered in PPD. We demonstrate that EV mRNA communication is robustly altered during pregnancy and the postpartum period in women who go on to develop PPD. Our work also establishes a direct link between reduced autophagy and PPD in patient samples. These data warrant investigating the feasibility of developing EV mRNA based biomarkers and therapeutic agents for PPD.

The immune phenotype of perinatal anxiety.

BACKGROUND: Immune dysregulation has been linked to both psychiatric illness and pregnancy morbidity, including perinatal depression, but little is known about the immune phenotype of perinatal anxiety. Here, we sought to identify the unique immune profile of antenatal anxiety. MATERIALS AND METHODS: Pregnant women (n = 107) were followed prospectively at 2nd and 3rd trimesters (T2, T3) and 6 weeks postpartum (PP6). Each visit included a blood draw and psychological evaluation, with clinical anxiety assessed using the Spielberg State-Trait Anxiety Scale. We enrolled both healthy controls and participants with anxiety alone; those with comorbid depression were excluded. Multiplex cytokine assays and flow cytometry were used to examine the association of anxiety symptoms with secreted immune markers and PBMC-derived immune cells. RESULTS: K cluster means revealed three clusters of anxiety symptomatology; due to low numbers in the highest severity anxiety group, these were collapsed into two groups: Non-Anxiety and Anxiety. Principal components analysis revealed two distinct clusters of cytokine secretion including one cluster that consisted of many innate immune cytokines and differed between groups. Compared to women in the Non-Anxiety group, women in the Anxiety group had lower levels of cytokine expression during pregnancy and an increase in levels into the postpartum, whereas Non-Anxiety women experienced a time-dependent decline. Immune cell populations also differed between our two groups, with the Anxiety group showing a decrease in the ratio of B cells to T cells from pregnancy to postpartum, whereas the Non-Anxiety women showed an increase in this ratio over time. Women in the Anxiety group also demonstrated an increased ratio of cytotoxic to helper T cells throughout pregnancy, a modest increase in the Th1:Th2 ratio across pregnancy, and a lower ratio of Th17:TREG cells in the postpartum as compared with Non-Anxiety women. CONCLUSION: These data suggest that the immune response throughout the antenatal period differs for women with anxiety symptoms compared to those without, suggestive of a unique immune phenotype of perinatal anxiety.

Perinatal Obsessive-Compulsive Disorder: Epidemiology, Phenomenology, Etiology, and Treatment.

PURPOSE OF REVIEW: We review recent evidence concerning the epidemiology, etiology, and treatment of obsessive-compulsive disorder (OCD) in the perinatal period. We examine studies reporting on rates of both new-onset OCD and exacerbation in both pregnancy and postpartum; explore both biological and psychosocial risk factors for the disorder; and review the latest evidence concerning treatment. RECENT FINDINGS: Evidence is limited in all areas, with rates of both OCD and subthreshold obsessive-compulsive symptoms varying widely across studies. Prevalence is likely higher in the perinatal period than in the general population. Clinical features in the perinatal period are more likely than at other times to concern harm to the child, with contamination and aggressive obsessions and cleaning and checking compulsions especially common. Research into the biological etiology is too limited at this time to be definitive. Both observational and randomized controlled trials support cognitive behavioral therapy with exposure and response prevention (CBT with ERP) as a first-line treatment, with limited evidence also supporting the use of selective serotonin reuptake inhibitors (SSRIs). Treatment considerations in the perinatal period must weigh the risks of treatment vs. the risks of untreated illness. Perinatal OCD is common and can be impairing. Clinical features differ somewhat compared to non-perinatal periods. Treatment does not differ from that used in the general population, though evidence pertaining specifically to the perinatal period is sparse.

Allopregnanolone and depression and anxiety symptoms across the peripartum: an exploratory study.

Recent research has implicated allopregnanolone (ALLO), a neuroactive steroid and metabolite of progesterone, in perinatal mood and anxiety symptoms. We sought to add to the limited literature examining ALLO and mood and anxiety at multiple time points across the peripartum. We measured mood and anxiety symptoms and ALLO levels by ELISA at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in N = 73 women with prior histories of mood and/or anxiety disorders and N = 38 healthy controls. Analytic methods included multivariate and logistic regressions with linear mixed effect models. Among all participants (N = 111), higher ALLO levels at W6 were associated with higher depression and anxiety scores: each one unit increase in log ALLO at W6 was associated with a 2.54 point increase on the Edinburgh Postnatal Depression Scale (EPDS) (95% CI: 0.73 to 4.33) and an 8.0 point increase on the Perinatal Anxiety Screening Scale (PASS) (95% CI: 3.82 to 12.6). In addition, the nature of the relationship between log ALLO level and psychological measures changed across time; from T2 to W6 for EPDS, ß = 3.73 (95% CI:1.16, 6.30), p = 0.0045; for PASS ß = 9.78 (95% CI:3.77, 15.79), p = 0.0014); from T3 to W6, for (EPDS, ß = 2.52 (95% CI:0.08, 4.96), p = 0.043; for PASS ß = 7.33 (95% CI:1.63, 13.02), p = 0.018). The relationship of log ALLO to mood and anxiety symptoms was the same among women with and without psychiatric histories. Our exploratory findings indicate that the relationship between ALLO and mood and anxiety symptoms may change across the peripartum.