Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Brexanolone therapeutics in post-partum depression involves inhibition of systemic inflammatory pathways.

BACKGROUND: Brexanolone has rapid, long-lasting, and remarkable efficacy in the treatment of post-partum depression (PPD). We test the hypothesis that brexanolone inhibits proinflammatory modulators and macrophage activation in PPD patients, which may promote clinical recovery. METHODS: PPD patients (N = 18) provided blood samples before and after brexanolone infusion according to the FDA-approved protocol. Patients were unresponsive to prior treatment before brexanolone therapy. Serum was collected to determine neurosteroid levels and whole blood cell lysates were examined for inflammatory markers and in vitro responses to the inflammatory activators lipopolysaccharide (LPS) and imiquimod (IMQ). FINDINGS: Brexanolone infusion altered multiple neuroactive steroid levels (N = 15-18), reduced levels of inflammatory mediators (N = 11) and inhibited their response to inflammatory immune activators (N = 9-11). Specifically, brexanolone infusion reduced whole blood cell tumor necrosis factor-α (TNF-α, p = 0.003), and interleukin-6 (IL-6, p = 0.04) and these effects were correlated with HAM-D score improvement (TNF-α, p = 0.049; IL-6, p = 0.02). Furthermore, brexanolone infusion prevented LPS and IMQ-induced elevation of TNF-α (LPS: p = 0.02; IMQ: p = 0.01), IL-1ß (LPS: p = 0.006; IMQ: p = 0.02) and IL-6 (LPS: p = 0.009; IMQ: p = 0.01), indicating inhibition of toll-like receptor (TLR)4 and TLR7 responses. Finally, inhibition of TNF-α, IL-1ß and IL-6 responses to both LPS and IMQ were correlated with HAM-D score improvements (p < 0.05). INTERPRETATION: Brexanolone actions involve inhibition of inflammatory mediator production and inhibition of inflammatory responses to TLR4 and TLR7 activators. The data suggest that inflammation plays a role in post-partum depression and that inhibition of inflammatory pathways contributes to the therapeutic efficacy of brexanolone. FUNDING: The Foundation of Hope, Raleigh, NC and UNC School of Medicine, Chapel Hill.

The longitudinal effects of stress and fear on psychiatric symptoms in mothers during the COVID-19 pandemic.

The COVID-19 pandemic has been particularly difficult for mothers. Women with a history of peripartum depression (PPD) may be vulnerable to relapse. We sought to understand changes in depressive and anxious symptoms throughout the pandemic and which stressors increased symptoms in women with a history of PPD. In June 2020, all US participants with a history of PPD (n = 12,007) in the global MomGenes Fight PPD study were invited to the COVID-19 follow-up study. Respondents (n = 2163, 18%) were sent biweekly and then monthly surveys until January 31, 2022. We employed time-varying effects models to evaluate trajectories of depressive (patient health questionnaire, PHQ-9) and anxious (generalized anxiety disorder, GAD-7) symptoms and to estimate longitudinal associations between perceived stress, fears, COVID-19 case rates, and symptoms. Peaks of PHQ-9, GAD-7, PSS, and perceived COVID-19 risk scores corresponded with timing of national COVID-19 case surges. High perceived stress was the strongest predictor of PHQ-9 (beta = 7.27; P = 1.48e - 38) and GAD-7 (beta = 7.73; P = 6.19e - 70). Feeling lack of control and unlikely to survive increased PHQ-9 and GAD-7 scores by 2 points. COVID-19 case rates, pandemic restrictions, and region were not independently associated with symptoms. This study suggests that the collective trauma of the pandemic has significantly affected mothers with a history of PPD, exemplified by high levels of perceived stress and the strong association with depressive and anxious symptoms. The next pandemic phase is uncertain, but will continue to influence mental health collectively and dynamically. Interventions must be flexible and responsive and should address fear, trauma, and feelings of control, particularly for mothers with a history of PPD.

App-Based Ecological Momentary Assessment to Enhance Clinical Care for Postpartum Depression: Pilot Acceptability Study.

BACKGROUND: Wearable tracking devices and mobile health technology are increasingly used in an effort to enhance clinical care and the delivery of personalized medical treatment. Postpartum depression is the most frequently diagnosed complication of childbirth; however, significant gaps in screening and treatment remain. OBJECTIVE: This study aims to investigate the clinical utility, predictive ability, and acceptability of using ecological momentary assessment to collect daily mood, sleep, and activity data through the use of an Apple Watch and mobile app among women with postpartum depression. METHODS: This was a pilot study consisting of 3 in-person research visits over the course of a 6-week enrollment period. Questionnaires to assess depression, anxiety, and maternal functioning were periodically collected, along with daily self-reported symptoms and passively collected physiological data via an Apple Watch. Feedback was collected from study participants and the study clinician to determine the utility and acceptability of daily tracking. Logistic regression was used to determine whether mood scores in the 2 weeks before a visit predicted scores at follow-up. Compliance with daily assessments was also measured. RESULTS: Of the 26 women enrolled, 23 (88%) completed the 6-week study period. On average, the participants completed 67% (34.4/51.5 days) of all active daily assessments and 74% (38/51.5 days) of all passive measures. Furthermore, all 23 participants completed the 3 required visits with the research team. Predictive correlations were found between self-reported mood and Edinburgh Postnatal Depression Scale score at follow-up, self-reported anxiety and EDPS, and sleep quality and Edinburgh Postnatal Depression Scale. CONCLUSIONS: Using ecological momentary assessment to track daily symptoms of postpartum depression using a wearable device was largely endorsed as acceptable and clinically useful by participants and the study clinician and could be an innovative solution to increase care access during the COVID-19 pandemic.

A Brexanolone Treatment Program at an Academic Medical Center: Patient Selection, 90-Day Posttreatment Outcomes, and Lessons Learned.

BACKGROUND: Brexanolone is the first U.S. Food and Drug Administration-approved drug for the treatment of postpartum depression. Brexanolone is a positive allosteric modulator of the GABAA receptor and is given over 60 hours by infusion in a medical setting. This drug has been shown to be effective at significantly reducing Hamilton Rating Scale for Depression scores at 60 hours and 30 days after infusion; however, data beyond 30 days have not yet been available. There have been limited clinical programs able to offer brexanolone owing to the complexity of setting up this treatment in a medical setting. PURPOSE: This study sought to obtain follow-up data from 16 patients who received a brexanolone infusion at UNC Hospitals in Chapel Hill, NC, between October 2019 and December 2020 and were beyond the 30-day postinfusion time point. We describe the methods used to successfully implement this treatment program in an academic medical center and discuss associated challenges and lessons learned with patient selection and process improvements. METHODS: Hamilton Rating Scale for Depression scores were collected before and after infusion from 16 patients who received a brexanolone infusion at UNC. Patients were subsequently contacted for a follow-up interview to obtain Hamilton Rating Scale for Depression scores and complete a semistructured interview at least 30 days past treatment end (between 3 and 16 months after infusion). RESULTS: All 16 patients had a significant reduction in Hamilton Rating Scale for Depression scores at 60 hours, scores dropping on average from 23.9 (standard deviation = 2.6) to 7.6 (standard deviation = 2.9). Eleven of 16 patients consented to provide follow-up data. Follow-up Hamilton Rating Scale for Depression scores remained lower than postinfusion at an average of 6.7 points (standard deviation = 5.1). CONCLUSION: With a strategic cross-disciplinary approach, a Clinical Brexanolone Treatment Program was established at UNC Hospitals in 2019. Sixteen patients have been treated in the program, and 11 participated in a follow-up interview. All 11 patients gave very positive feedback about their treatment. Our program has found brexanolone to be a useful clinical tool in treating women with significant symptoms of postpartum depression.

PPD ACT: an app-based genetic study of postpartum depression.

Postpartum depression (PPD) is one of the most frequent complications of childbirth and particularly is suited to genetic investigation as it is more homogenous than major depression outside of the perinatal period. We developed an iOS app (PPD ACT) to recruit, consent, screen, and enable DNA collection from women with a lifetime history of PPD to sufficiently power genome-wide association studies. In 1 year, we recruited 7344 women with a history of PPD and have biobanked 2946 DNA samples from the US. This sample of PPD cases was notably severely affected and within 2 years of their worst episode of PPD. Clinical validation was performed within a hospital setting on a subset of participants and recall validity assessed 6-9 months after initial assessment to ensure reliability of screening tools. Here we detail the creation of the PPD ACT mobile app including design, ethical, security, and deployment considerations. We emphasize the importance of multidisciplinary collaboration to correctly implement such a research project. Additionally, we describe our ability to customize the PPD ACT platform to deploy internationally in order to collect a global sample of women with PPD.

Maternal and infant outcomes associated with lithium use in pregnancy: an international collaborative meta-analysis of six cohort studies.

BACKGROUND: Concerns about teratogenicity and maternal and offspring complications restrict the use of lithium during pregnancy for the treatment of mood disorders. We aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity, and congenital malformations. METHODS: In this meta-analysis, primary data from pregnant women and their children from six international cohorts based in the community (Denmark, Sweden, and Ontario, Canada) and in clinics (the Netherlands, UK, and USA) were analysed. Pregnancies were eligible for analysis if the pregnancy resulted in a liveborn singleton between 1997 and 2015, if health-related information was available for both mother and infant, and if the mother had a mood disorder (bipolar disorder or major depressive disorder) or if she had been given lithium during pregnancy (at least two dispensations of lithium during pregnancy that were dispensed any time from 1 month before conception until the delivery, or a single lithium dispensation during pregnancy when there was at least one other lithium dispensation within 6 months before or after this date). Pregnancies during which the mother had been prescribed known teratogenic drugs were excluded. Pregnancies were grouped into a lithium-exposed group and a mood disorder reference group. The main outcome measures were pregnancy complications, delivery outcomes, neonatal readmission to hospital within 28 days of birth, and congenital malformations (major malformations and major cardiac malformations). Analyses were done at each site by use of a shared protocol. Adjusted odds ratios (aORs) and 95% CIs were calculated by use of logistic regression models, and site-specific prevalence rates and ORs were pooled by use of random-effects meta-analytical models. FINDINGS: 22   124 eligible pregnancies were identified across the six cohorts, of which 727 pregnancies were eligible for inclusion in the lithium-exposed group (557 [77%] from register-based cohorts and 170 [23%] from clinical cohorts). Lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. An increased risk for neonatal readmission within 28 days of birth was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27·5% [95% CI 15·8-39·1] vs 14·3% [10·4-18·2]; pooled aOR 1·62, 95% CI 1·12-2·33). Lithium exposure during the first trimester was associated with an increased risk of major malformations (pooled prevalence 7·4% [95% CI 4·0-10·7] vs 4·3% [3·7-4·8]; pooled aOR 1·71, 95% CI 1·07-2·72) but for major cardiac malformations the difference was not significant (2·1% [0·5-3·7] vs 1·6% [1·0-2·1]; pooled aOR 1·54, 95% CI 0·64-3·70). INTERPRETATION: Considering both the effect sizes and the precision of the estimates in this meta-analysis, treatment decisions for pregnant women with mood disorders must weigh the potential for increased risks of lithium during pregnancy-in particular those associated with use of lithium during the first trimester-against its effectiveness at reducing relapse. FUNDING: None.